Sarm1 inhibitors

Abstract

The present invention provides compounds having the general formula (I) wherein X, Y, Z, U, V and R1 to R7 are as described herein, compositions comprising the compounds, methods of making the compounds, and methods of using the compounds in the treatment or prevention of diseases associated with SARM1.

Description

(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) ™ (19) World Intellectual Property ~S Organization ; LUAU A AC ATA A International Bureau —— (10) International Publication Number (43) International Publication Date —— WO 2025 / 012296 Al 16 January 2025 (16.01.2025) WIPOIPCT (51) International Patent Classification: mann-La Roche AG, Grenzacherstrasse 124, 4070 Basel CO7D 405 / 12 (2006.01) A61P 25 / 00 (2006.01) (CH). STEINER, Sandra; c / o F. Hoffmann-La Roche AG, CO7D 405 / 14 (2006.01) Grenzacherstrasse 124, 4070 Basel (CH). ZAMBALDO, (21) International Application Number: Claudio; c / o F. Hoffmann-La Roche AG, Grenzacherstrasse “PCT / EP2024 / 069422 124, 4070 Basel (CH). . oe . (74) Agent: NEUHAUS, Dr. Christian; c / o F. Hoffmann-La (22) International Filing Date: 10 July 2024 (10.07.2024 Roche AG, Patent Department, Grenzacherstrasse 124, uly 2024 (10.07.2024) 4070 Basel (CH). ° esignated States (unless otherwise indicated, for every (25) Filing Language:English (81) D as (unl h d d (26) Publication Language: English kind of national protection available); AE, AG, AL, AM, (30) Priority Data: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, . A, CH, CL, CN. R. Z, DE, DJ, DK, DM 23 185006.6 12 July 2023 (12.07.2023) EP ie ae ne mY ro Ne Wop cp GE on GM CT. 23219575.0 22 December 2023 (22.12.2023) EP HN, HR. HU, ID, IL, IN, IQ, IR, IS, IT, JM, JO, JP, KE, KG, (71) Applicant (for all designated States except US): F. HOFF- KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MANN-LA ROCHE AG [CH / CH], Grenzacherstrasse MA, MD, MG, MK, MN, MU, MW, MX, MY, MZ, NA, 124, 4070 Basel (CH). NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, (71) Applicant (for US only): HOFFMANN-LA ROCHE TI] TM TN TR IT TZ.UA.UG US. UZ. VC. VN WS INC. [US / US]; Overlook at Great Notch, 150 Clove Road, Z A 7M A in — 8th Floor, Suite 8 - Legal Department, Little Falls, New Jer- ee -—— sey 07424 (US). (84)Designated States (unless otherwise indicated, for every =— (72) Inventors: AREGGER, Nina; c / o F. Hoffmann-La Roche kind of regional protection available): ARIPO (BW, CV, — ; > Nina, io' ; GH, GM, KE, LR, LS, MW, MZ, NA, ST, ST, SD, SD, — — AG, Grenzacherstrasse 124, 4070 Basel (CH BENZ, Jo- SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ = erg; c / o F. Hoffmann-La Roche AG, Grenzacherstrasse RU TI. TM) European (AL, BY. 124, 4070 CARAMENTI, Paola; (CH). GASSER, Claire Julie; c / o F. Hoffmann-La Roche SI SK SM TR) O API (BF.B j CF CG Cl CM GA GN. =— AG, Grenzacherstrasse 124, 4070 Basel (CH). Hoffmann-La Roche AG, Grenzacherstrasse ; 0 ' = 124, 4070 Basel (CH GRETHER, Uwe Michael c / o Published: — F. Hoffmann-La Roche AG;Grenzacherstrasse 124, 4070 “th ° ternational h + Art 213 —— Basel (CH). HAAP, Wolfgang; c / o F. Hoffmann-La Roche — with international search report (Art. 21(3)) — AG, Grenzacherstrasse 124, 4070 Basel (CH). KEANEY, — James Martin; c / o F. Hoffmann-La Roche AG, Gren- — zacherstrasse 124, 4070 Basel (CH). c / o F. Hoffmann-La Roche 124, 4070 Basel (CH). ROMBACH, Didier, c / o = F. Hoffmann-La Roche AG, Grenzacherstrasse 124, 4070 — Basel (CH). SCHMID, Philip Claudio; c / o F. Hoff- w= (54) Title: SARM1 INHIBITORS < 5 (57) Abstract: The invention provides compounds having the general formula (1) a ON Db da R'? R sb where X, Y, Z, U, V, and R! to R' are as described herein, compositions including N 1 R@ R YU RR the compounds, processes of manufacturing the compounds andmethods of using the5 Nn R XO JL UV O compounds in the treatment or prevention of diseases that are associated with SARM1. N N = rx | lz, =H por ih Nave? R a7 Ba a a) N WO 2025 / 012296 PCT / EP2024 / 069422 SARM1 INHIBITORS Field of the Invention The present invention relates to organic compounds useful for therapy or prophylaxis in a mammal, and in particular to Sterile Alpha And TIR Motif Containing 1 (SARM1) inhibitors for 5 the treatment or prevention of amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie- Tooth disease. Background of the Invention 10 Axonal degeneration is a central driver of disability and disease progression in neurodegenerative and neurological disorders including multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), frontotemporal dementia, Parkinson’s disease,Alzheimer’s disease and peripheral neuropathies. Due to their high energy demands in order to propagate action potentials and ensure protein transport over sometimes meter-long distances, axons are particularly 15 sensitive to metabolic stress following for example mitochondrial disruption or microtubule disassembly. Instead of being a passive dying process however, the resulting axonal degeneration is now understood to involve key molecular components and steps. Programmed axonal degeneration, also known as Wallerian degeneration, is a key molecular mechanism driving axonal loss. As an early pathological feature of numerous neurological conditions 20 associated with an increasing societal and economic burden, therapeutic approaches to target the prevention of axonal degeneration therefore hold significant treatment potential. Summary of the Invention In a first aspect, the present invention provides compounds of formula (I) WO 2025 / 012296 PCT / EP2024 / 069422 -2- 2b 4a R Re 1 re RU R ReRy X JL V 3 6b N Z R 7 R Sy7 R Rea ; (1) wherein X, Y, Z, U, V, and R! to R’ are as defined herein. In further aspects, the invention provides compositions including the compounds of formula (1), processes of manufacturing the compounds of formula (I) and methods of using the compounds 5 of formula (1). Detailed Description of the Invention Definitions Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be 10 understood to be applicable to any other aspect, embodiment or example described herein, unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention 1s not restricted to thedetails of 15 any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed. The term “alkyl” refers to a mono- or multivalent, e.g., a mono- or bivalent, linear or branched 20 saturated hydrocarbon group of 1 to 6 carbon atoms (“C).6-alkyl”), e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, the alkyl group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non- limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. Particularly preferred, yet non-limiting examples 25 of alkyl are methyl, tert-butyl, and 2,2-dimethylpropyl. WO 2025 / 012296 PCT / EP2024 / 069422 -3- Theterm “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1 to 6 carbon atoms (“Ci.6-alkoxy’”). In some embodiments, the alkoxy group contains 1 to 4 carbon atoms, e.g., 1, 2, 3, or 4 carbon atoms. In other embodiments, the alkoxy group contains 1 5 to3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. A particularly preferred, yet non- limiting example of alkoxy is methoxy. The term “haloalkoxy” refers to an alkoxy group, wherein at least one of the hydrogen atoms of the alkoxy group has been replaced by a halogen atom, preferably fluoro. Preferably, 10 “haloalkoxy” refers to an alkoxy group wherein 1, 2 or 3 hydrogen atoms of the alkoxy group have been replaced by a halogen atom, most preferably fluoro. Prticularly preferred, yet non- limiting examples of haloalkoxy aretrifluoromethoxy, 3,3,3-trifluoropropoxy, 2,2,2-trifluoro-1- methyl-ethoxy, and 3-fluoro-2-fluoro-propoxy. The term “alkoxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of 15 the alkyl group has been replaced by an alkoxy group. Preferably, “alkoxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by an alkoxy group. Some particularly preferred, yet non-limiting examples of alkoxyalkyl are 2-methoxy-2,2-dimethyl-ethyl, methoxymethyl, and 2- methoxyethyl. 20 The term “haloalkoxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a haloalkoxy group. Preferably, “haloalkoxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl group have been replaced by a haloalkoxy group. Particularly preferred, yet non-limiting examples of haloalkoxyalkyl aredifluoromethoxymethyl and trifluoromethoxymethyl. 25 Theterm “halogen” or “halo” refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term “halogen” or “halo” refers to fluoro (F), chloro (Cl) or bromo (Br). Particularly preferred, yet non-limiting examples of “halogen” or “halo” are fluoro (F) and chloro (Cl). The term “cyano” refers to a —CN (nitrile) group. 30 The term “hydroxy” refers to an -OH group. WO 2025 / 012296 PCT / EP2024 / 069422 -4- The term “cycloalkyl” as used herein refers to a saturated monocyclic or bicyclic hydrocarbon group of 3 to 10 ring carbon atoms (“C3-10-cycloalkyl”). In some preferred embodiments, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 8 ring carbon atoms. “Bicyclic cycloalkyl” refers to cycloalkyl moieties consisting of two saturated carbocycles having two 5 carbon atoms in common, i.e., the bridge separating the two rings 1s either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties,1.¢e., the two rings are connected via one common ring atom. Preferably, the cycloalkyl group is a monocyclic hydrocarbon group of 3 to 6 ring carbon atoms, e.g., of 3, 4, 5 or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 1- 10 bicyclo[1.1.1]pentanyl, norbornanyl, and 1-bicyclo[2.2.2]octanyl. Particularly preferred, yet non- limiting examples of cycloalkyl are cyclopropyl, bicyclo[1.1.1]pentanyl and cyclohexyl. The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members (“C6-Cjo-aryl”), wherein at least one ring in the system is aromatic. Some non-limiting examples of aryl include phenyl and 9H-fluorenyl (e.g. 9H-fluoren-9-yl). A 15 particularly preferred, yet non-limiting example of aryl is phenyl. The term “aroyl” refers to an aryl moiety that is bound to the parent moiety via a carbonyl group. A preferred, yet non-limiting example ofaroyl is benzoyl. The term “heteroaroyl” refers to a heteroaryl moiety that is bound to the parent moiety via a carbonyl group. A preferred, yet non-limiting example of heteroaroyl is pyridine-3-carbony]. 20 The term "heteroaryl" refers to a mono- or multivalent, monocyclic, bicyclic or tricyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 12 ring members, for example 5 to 11, 5 to 10, 5 to 9, 5 to 8, 5 to 7 or 5 to 6 ring members, wherein at least one ring in the system is aromatic, and at least one ring in the system contains one or more heteroatoms. Preferably, “heteroaryl” refers to a 5-9 membered heteroaryl comprising 1, 2, 3 or 4 25 heteroatoms independently selected from O, S and N. Most preferably, “heteroaryl” refers to a 5- 6 membered heteroaryl comprising 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl,1,3-benzoxazol-2-yl, 1,3-benzoxazol-4-yl, 1,3-benzoxazol-5-yl, 1,3-benzoxazol-6-yl, 1,3-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, oxadiazolyl (e.g. 1,2,4-oxadiazol-3-yl, 30 ~—-:1,3,4-oxadiazol-2-yl), pyrazolyl (e.g. 1H-pyrazol-4-yl), triazolyl (e.g. 1H-1,2,4-triazol-3-yl, 1H- triazol-4-yl, 2H-triazol-4-yl), and tetrazolyl (e.g. 2H-tetrazol-5-yl). WO 2025 / 012296 PCT / EP2024 / 069422 -5- The term “heterocyclyl” as used herein refers to a saturated or partly unsaturated mono- or bicyclic, preferably monocyclic ring system of 3 to 14 ring atoms, e.g. 3 to 13, 3 to 12, 3 to 11, 3 to 10, 3 to 9, 3 to 8, 3 to 7, 3 to 6 or 3 to 5 ring atoms, preferably 3 to 10 ring atoms, more preferably 3 to 10 ring atoms, most preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring 5 atoms are heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, the remaining ring atoms being carbon. “Bicyclic heterocyclyl”refers to heterocyclic moieties consisting of two cycles having two ring atoms in common, 1.e., the bridge separating the two rings is either a single bond or a chain of one or two ring atoms, and to spirocyclic moieties, 1.¢e., the two rings are connected via 10 one common ring atom. Some non-limiting examples of monocyclic heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, 2-azaspiro[3.3 ]heptan-2-yl, 2,6-diazaspiro[3.3]heptan-2-yl, 2- azaspiro[3.4]octan-2-yl, 5-oxa-2-azaspiro[3 .4]octan-2-yl, pyrrolidinyl (e.g. pyrrolidin-1-yl), thiomorpholino, oxetan-3-yl, oxetan-2-yl, tetrahydrofuranyl (e.g. tetrahydrofuran-2-yl), tetrahydropyranyl (e.g. tetrahydropyran-2-yl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- 15 piperidinyl, piperazinyl (e.g. piperazin-1-yl), morpholino, morpholin-2-yl and morpholin-3-yl. The term “haloalkyl” refers to an alkyl group as defined herein, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a halogen atom,preferably fluoro. Preferably, “haloalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms of the alkyl group have been replaced by a halogen atom, most preferably fluoro. Particularly preferred, yet 20 non-limiting examples of haloalkyl are trifluoromethyl, difluoromethyl, 1,1-difluoroethyl, 2,2- difluoroethyl, and 2,2,2-trifluoroethyl. The term “hydroxyalkyl” refers to an alkyl group, wherein at least one of the hydrogen atoms of the alkyl group has been replaced by a hydroxy group. Preferably, “hydroxyalkyl” refers to an alkyl group wherein 1, 2 or 3 hydrogen atoms, most preferably 1 hydrogen atom of the alkyl 25 group have been replaced by a hydroxy group. Preferred, yet non-limiting examples of hydroxyalkyl are 2-hydroxy-1,1-dimethylethyl, 2-hydroxy-2-methyl-propyl, hydroxymethyl and hydroxyethyl (e.g. 2-hydroxyethyl). The term "pharmaceutically acceptable salt" refers to those salts which retain the biological effectiveness and properties of the free bases or freeacids, which are not biologically or 30 otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, in particular hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic WO 2025 / 012296 PCT / EP2024 / 069422 -6- acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, N-acetylcystein and the like. In addition these salts may be prepared by addition of an inorganic base or an organic base to the free acid. Salts derived from 5 an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calctum, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 10 lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. The compounds of formula (I) can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereioisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. 15 The abbreviation “SARM1” refers to Sterile Alpha and TIR Motif Containing 1. The term “treatment” as used herein includes: (1) inhibiting the state, disorder or condition (e.g. arresting, reducing or delaying the development of the disease, or a relapse thereof in case of maintenance treatment, of at least one clinical or subclinical symptom thereof); and / or (2) relieving thecondition (1.e., causing regression of the state, disorder or condition or at least one 20 of its clinical or subclinical symptoms). The benefit to a patient to be treated is either statistically significant or at least perceptible to the patient or to the physician. However, it will be appreciated that when a medicament is administered to a patient to treat a disease, the outcome may not always be effective treatment. The term “prophylaxis” as used herein includes: preventing or delaying the appearance of 25 clinical symptoms of the state, disorder or condition developing in a mammal and especially a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition. SARM1 Axonal breakdown distal to the site of an injury is a key feature of programmed axonal 30 degeneration or Wallerian degeneration and is characterized by mitochondrial disruption, loss of WO2025 / 012296 PCT / EP2024 / 069422 -7- nicotinamide adenine dinucleotide (NAD+), increased intracellular calcium levels and axonal fragmentation (Conforti, L., et al., Nat. Rev. Neurosci., 2014, 15, 394-409). The central component of the programmed axonal degeneration mechanism is Sterile Alpha And TIR Motif Containing 1 (SARM1) (Osterloh, J.M., et al., Science, 2012, 337, 481-484). SARM1 is an 5 NAD+ hydrolase that depletes levels of NAD+ by cleaving it into the metabolites: nicotinamide (NAM) and adenosine diphosphate ribose (ADPR) or cyclic ADPR. The resulting loss of NAD+, an essential metabolite involved in energy metabolism and axonal homeostasis (Hopkins, E.L., et al., 2021, Front. Mol. Biosci., 8:703532), and increase in cADPR, a modulator of intra-axonal calcium levels (Li, Y., et al., 2022, J. Cell Biol., 221, e202106080), contributes to the subsequent 10 axonal degeneration process. Other molecular components of the Wallerian axonal degeneration pathway have been identifiedincluding axonal survival factors like nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2). Under normal conditions, axonal survival factors such as NMNAT2 are continuously turned over and replenished by anterograde transport along the axon from the cell 15 body (Gilley, J. & Coleman, M.P., 2010, PLoS Biol., 8, e€1000300). NUNAT2 maintains axonal energetics by catalyzing the formation of NAD+ from nicotinamide mononucleotide (NMN) and adenosine tri-phosphate (ATP). However during injury or disease, disruption of microtubule assembly or mitochondrial depolarization in axons leads to loss of NUNAT2 transport followed by NMNAT2 depletion. SARM1 is activated in turn by reduced NMUNAT2 levels as a result of 20 loss of NAD+, a negative SARM1 ligand, and accumulation of NMN, a positive SARM1 ligand (Figley, M.D., et al., 2021, Neuron, 109, 1118-1136). SARM1 is a multidomain protein consisting of an autoinhibitory ARM domain, tandem oligomerization SAM domains and a catalytic TIRdomain. While originally thought to exist as a monomer in solution, recent high-resolution cryo-EM structures have revealed that SARM1 25 exists as an octamer with the ARM domains locking the TIR domains in an inactive conformation (Bratkowski, M., et al., 2020, Ce / / Rep., 32, 107999). This was followed by identification of an allosteric site in which both NMN and NAD+ can bind (Jiang, Y., et al., 2020, Nature, 588, 658-663; Figley, M.D., et al., 2021, Neuron, 109, 1118-1136). The increase in NMN / NAD+ during axonal injury and the higher affinity of NUN for SARM1 results in 30 replacement of NAD+ in the allosteric pocket, releasing the ARM domains and allowing for TIR domain catalytic activity. WO 2025 / 012296 PCT / EP2024 / 069422 -8- Both in vitro and in vivo studies of SARM1 loss-of-function have highlighted the central role of SARM1 in programmed axonal degeneration. SARM1 genetic knockout has been shown to protect axons in both human and rodent neuronal cultures following physical(axotomy) or chemical injury, for example due to chemotherapeutic drugs such as vincristine (Osterloh, J.M., 5 etal., Science, 2012, 337, 481-484; Chen, Y., et al., 2021, Exp. Neurol., 339, 113636). In vivo, deletion of SARM1 prevents nerve fiber loss and restores normal pain sensitivity in models of chemotherapy-induced peripheral neuropathy (Geisler, S., et al., 2016, Brain, 139, 3092-3108) and diabetic peripheral neuropathy (Cheng, Y., et al., 2019, Diabetes, 68, 2120-2130). SARM1 deletion also attenuates axonal degeneration in pre-clinical models of ALS (White, M.A., et al., 10 Acta Neuropathol. Commun., 7, 166) and MS (Viar, K., et al., 2020, PLoS One, 15, e0235110). In models of eye disorders, SARM1 deficiency has been found to block loss of axons of retinal ganglion cells in glaucoma models (Finnegan, L.K., et al., 2022, Int. J. Mol. Sci., 23, 1606) and of photoreceptors in retinitis pigmentosa models (Ozaki, E., et al., 2020, Life Sci. Alliance., 3, e201900618). These combinedstudies underscore the therapeutic potential of blocking SARM1 15 activity to ameliorate various neurological disorders associated with axonal loss. Compounds of the Invention In a first aspect, the present invention provides a compound of formula (I) 2b 4a R Re : . R22 R tL - Rod N Sy UZ R a7 ea R (1) or a pharmaceutically acceptable salt thereof, wherein: 20 X, Y and Z are each selected from CR“ and N, provided that at most two of X, Y and Z are N; U _ isselected from O, S, and NRY; V___isacovalent bond or C(R‘)»; A is selected from 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, Ce- 25 Cio-aryl and C3-Cjo0-cycloalkyl; L is selected from a covalent bond, -CH2—, and -NR!-: R’ is selected from hydrogen and C1-Co-alky]; R" _ is selected from hydrogen, C1-C¢-alkyl and cyano; WO 2025 / 012296 PCT / EP2024 / 069422 -9. each RY is independently selected from hydrogen, C1-C¢-alkyl and halo-C\-Co-alky]; R“ is selected from hydrogen and C1-Co-alky]; R! is selected from hydrogen,halogen, cyano, C1-Co-alkyl, C2-Ce-alkenyl, C2-Co- alkynyl, halo-C1-Ce-alkyl, hydroxy-Ci-Ce-alkyl, Ci-Co-alkoxy, halo-Ci-Ce-alkoxy, R'2 \y 5 and a group il : R'* is selected from hydrogen, halogen, C1-C6-alkyl, and halo-Ci-Ce-alkyl; R* and R”? are each independently selected from hydrogen, C1-C¢-alkyl, halo-C1-C6-alkyl, C1-Ce-alkoxy, halo-C)-Ce6-alkoxy, C1-Ce-alkyl-NH-C1-Ce-alkyl-, C3-Ci0-cycloalkyl, C3-C10-cycloalkyl-Ci-Co-alkyl, Co-Cio-aryl, Co-C10-aryl-Ci-Co-alkyl, and R?°-O-C1- 10 Co-alkyl; wherein each Co-Cio-aryl and C3-Cio-cycloalkyl is optionally substituted with 1-2 halogen substituents or R* and R”?, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; R* is selected from hydrogen, C1-Co-alkyl, halo-Ci-C6-alkyl, and Co-Cio-aryl; wherein 15 said Cs-Cjo-aryl is optionally substituted with 1-2 halogen substituents; R? is selected from hydrogen, C1-C¢-alkyl, halo-Ci-Ce-alkyl, and C3-C10-cycloalkyl; R* and R® are each independently selectedfrom hydrogen, halogen, hydroxy, C1-Co- alkyl, 5- to 14-membered heteroaryl, Ce-Cio-aryl, Ce-C10-aroyl, 5- to 14-membered heteroaroyl; wherein said 5- to 14-membered heteroaryl, Cs-Cio-aryl, C6-Cio-aroyl, 20 5- to 14-membered heteroaroyl are optionally substituted with 1-3 substituents independently selected from halogen and hydroxy-C-C¢-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl or a 3- to 14-membered heterocyclyl, wherein said C3-Ci0-cycloalkyl and 3- to 14-membered heterocyclyl are optionally substituted with 1-3 halogen 25 substituents; or R* and R’, taken together with the carbon atoms to which they are attached, form a Cs- Cyo-cycloalkyl; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- 30 Cio-cycloalkyl or oxo; R® and R°® are each independently selected from hydrogen, 5- to 14-memberedheteroaryl, and Ce6-Cio-aryl; wherein said 5- to 14-membered heteroaryl, and Ce-Cio-aryl are WO 2025 / 012296 PCT / EP2024 / 069422 -10- optionally substituted with 1-3 substituents independently selected from halogen, C1- Ce-alkyl, halo-Ci-Ce6-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; and R’ _ is selected hydrogen, C1-C¢-alkyl, halo-C1-Co-alkyl, and 5- to 14~-membered 5 heteroaryl. In one embodiment, the present invention provides a compound of Formula (I) as described herein, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are N; 10 U _ isselected from O, S, and NRY; V___isacovalent bond or C(R‘)»; A is selected from 3- to 14-membered heterocyclyl, 5- to 14-membered heteroaryl, Ce- Cio-aryl and C3-Cio-cycloalkyl; L ___ isselected from a covalent bond and —NR‘-; 15 R’ is selected from hydrogen and C1-Co-alky]; R" _ is selected from hydrogen, C1-C¢-alkyl and cyano; each RY is independently selected from hydrogen, C1-C¢-alkyl andhalo-C\-Co-alky]; R! is selected from hydrogen, halogen, cyano, Ci-C¢-alkyl, halo-C1-Ce-alkyl, hydroxy- R'2 \y C1-Ce-alkyl, Ci-Ce-alkoxy, halo-C1-Ce¢-alkoxy, and a group il ; 20 R!* is selected from hydrogen, halogen, and Ci-Co-alky]; R* and R”? are each independently selected from hydrogen, C1-C¢-alkyl, halo-C1-C6-alkyl, C1-Ce-alkoxy, halo-C)-Ce6-alkoxy, C1-Ce-alkyl-NH-C1-Ce-alkyl-, C3-Ci0-cycloalkyl, and R°-O-C1-C¢-alkyl; or R* and R”?, taken together with the carbon atom to which they are attached, form a C3- 25 Cyo-cycloalkyl; R* is selected from hydrogen, C1-Co-alkyl, halo-C-Cs-alkyl, and C6-C1o-ary]; R? _ is selected from hydrogen, C1-Ce-alkyl, and C3-Cio-cycloalkyl; R* and R® are each independently selected from hydrogen, halogen, hydroxy, C1-Co- alkyl, 5- to 14-membered heteroaryl, Ce-Cio-aryl, Ce-C10-aroyl, 5- to 14-membered 30 heteroaroyl; wherein said 5- to 14-membered heteroaryl, Cs-Cio-aryl, C6-Cio-aroyl, WO 2025 / 012296 PCT / EP2024 / 069422 -ll- 5- to 14-membered heteroaroylare optionally substituted with 1-3 substituents independently selected from halogen and hydroxy-C-C¢-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl or a 3- to 14-membered heterocyclyl, wherein said C3-Ci0-cycloalkyl 5 and 3- to 14-membered heterocyclyl are optionally substituted with 1-3 halogen substituents; or R* and R’, taken together with the carbon atoms to which they are attached, form a Cs- Cyo-cycloalkyl; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or 10 R** and R°®, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; R® and R°® are each independently selected from hydrogen, 5- to 14-membered heteroaryl, and Ce6-Cio-aryl; wherein said 5- to 14-membered heteroaryl, and Ce-Cio-aryl are optionally substituted with 1-3 substituents independently selected from halogen, C1- 15 Ce-alkyl, halo-Ci-Ce6-alkyl, C3-Cio-cycloalkyl, and 5- to 14-memberedheteroaryl; and R’ _ is selected hydrogen, C1-C¢-alkyl, halo-C1-Co-alkyl, and 5- to 14~-membered heteroaryl. In a preferred embodiment, the present invention provides a compound of Formula (I) as 20 described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of Formula (I) is a compound of Formula (Ia) Rib R°? R’2 5b RA Ro R Ri XO JL Le i ro We Sy- (Ia) or a pharmaceutically acceptable salt thereof, wherein: X, Y and Z are each selected from CH and N, provided that at most two of X, Y and Z are 25 N; R! is selected from hydrogen, halogen, cyano, C1-C¢-alkyl, halo-Ci-Ce-alkyl, and Cs- Cyo-cycloalkyl; WO 2025 / 012296 PCT / EP2024 / 069422 -12- R* and R”? are each independently selected from hydrogen, C1-C¢-alkyl, halo-C1-C6-alkyl, C1-Ce-alkoxy, halo-C)-Ce6-alkoxy, Ci-Ce-alkyl-NH-C1-Ce-alkyl-, Ci-Ce-alkoxy-C1- Co-alkyl, and halo-C1-Ce-alkoxy-C1-Ce-alkyl; or R* and R”?, taken together with the carbon atom to which they are attached, form a C3- 5 Cyo-cycloalkyl; R? _ isselected from hydrogen, C1-Ce-alkyl, and C3-Cio-cycloalkyl; R* and R® are each independently selected from hydrogen, halogen, hydroxy, C1-Co- alkyl, 5- to 14-membered heteroaryl, Ce-Cio-aryl, Ce-C10-aroyl, 5- to 14-membered heteroaroyl; wherein said 5- to 14-membered heteroaryl, Cs-Cio-aryl, C6-Cio-aroyl, 10 5- to 14-membered heteroaroyl are optionally substituted with 1-3 substituents independently selected from halogen and hydroxy-C-C¢-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl or a 3- to 14-membered heterocyclyl, wherein said C3-Ci0-cycloalkyl and 3- to 14-membered heterocyclyl are optionally substituted with 1-3 halogen 15 substituents; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; R® and R°® are each independently selected from hydrogen, 5- to 14-membered heteroaryl, 20 andCe6-Cio-aryl; wherein said 5- to 14-membered heteroaryl, and Ce-Cio-aryl are optionally substituted with 1-3 substituents independently selected from halogen, C1- Ce-alkyl, halo-Ci-Ce6-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; and R’ _ is selected hydrogen, C1-C¢-alkyl, halo-C1-Co-alkyl, and 5- to 14~-membered 25 heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; or 30. (ili), ~Xis N and Y and Z are CH; or (iv) XisCH and Y and Z are N; or (v) Xand Y are N and Z is CH; or (vi) X and Z are N and Y is CH. WO 2025 / 012296 PCT / EP2024 / 069422 -13- In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) Xand Y are CH and Z is CR“; wherein R% is selected from hydrogen and Ci-Co-alkyl; or (ii) X and Z are CH and Yis N; or 5 (iti) Xis N and Y and Z are CH. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; or 10 (iti) Xis N and Y and Z are CH. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y are CH and Z is CR“; wherein R% is selected from hydrogen and methy]; or (ii) Xand Z are CH and Y is N. 15 Ina preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or (ii) Xand Z are CH and Y is N. In a particularly preferred embodiment, the present invention provides a compound of formula 20 (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are CH. In a particularlypreferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein X and Z are CH and YisN. In one embodiment, the present invention provides a compound of formula (I) as defined herein, 25 ora pharmaceutically acceptable salt thereof, wherein: R! _ is selected from hydrogen, halogen, cyano, C1-Co-alkyl, C2-Ce-alkynyl, halo-C1-Co- alkyl, hydroxy-C1-Ce-alkyl, Ci-Ce-alkoxy, and a group ; WO 2025 / 012296 PCT / EP2024 / 069422 -14- A is selected from 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, phenyl, and C3-C¢-cycloalkyl; L is selected from a covalent bond, -CH2—, and -NR!-: 5 R’ is hydrogen; and R!* is selected from hydrogen, halogen, C1-Co-alkyl, and halo-C1-C¢-alkyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or apharmaceutically acceptable salt thereof, wherein: R! _ is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, prop-1-ynyl, 10 hydroxymethyl, CHF2, methoxy, and a group ; A is selected from azetidine, tetrahydrofurane, tetrahydropyrane, pyrrolidine, pyrazole, phenyl, pyridyl, and cyclopropyl; L is selected from a covalent bond, -CH2—, and -NR!-: R’ is hydrogen; and 15 R!* is selected from hydrogen, chloro, methyl, and CF3. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R! _ is selected from hydrogen, halogen, cyano, C1-C¢-alkyl, halo-C1-Co-alkyl, hydroxy- C1-Ce-alkyl, Ci-Co-alkoxy, and a group ; 20 A is selected from 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, phenyl, and C3-C¢-cycloalkyl; L ___ isselected from a covalent bond and —NR‘-; R’is hydrogen; and 25 R!* is selected from hydrogen, halogen, and Ci-Co-alkyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R! is selected from hydrogen, halogen, cyano, Ci-Ce-alkyl, and C3-Cjo-cycloalkyl. WO 2025 / 012296 PCT / EP2024 / 069422 -15- In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R! is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, CHF2, methoxy, and a group ; 5 A _ isselected from azetidine, pyrrolidine, pyrazole, phenyl, and cyclopropyl; L ___ isselected from a covalent bond and —NR‘-; R’ is hydrogen; and R!* is selected from hydrogen, chloro, and methyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, 10 ora pharmaceutically acceptable salt thereof, wherein R! is selected from hydrogen, fluoro,chloro, cyano, methyl, and cyclopropyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R! is selected from hydrogen, halogen, and C1-Ce¢-alkyl. 15 Ina particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R! is selected from hydrogen, fluoro, and methyl. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R! is hydrogen. 20 In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, C1-C¢-alkyl, halo-C)-Co-alkyl, C1-Co-alkyl-NH-Ci-Co- alkyl-, C3-Cio-cycloalkyl, phenyl-Ci-Co-alkyl, and R?°-O-C1-Ce-alkyl; wherein said phenyl isoptionally substituted with 1 halogen substituent; 25 Ris hydrogen; and R* is selected from hydrogen, C1-C¢-alkyl, halo-C1-Ce-alkyl, and phenyl; wherein said phenyl is optionally substituted with 1 halogen substituent; or R* and R”°, taken together with the carbon atom to which they are attached, form a C3-Co- cycloalkyl. WO 2025 / 012296 PCT / EP2024 / 069422 -16- In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH2CHF2, CH3N-CH>-, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethy]l, 5 fluorophenylethyl, CHF2-O-CHo-, CF3-O-CH2-, and cyclopropyl; and R?? is hydrogen; or R* and R”°, taken together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, 10 ora pharmaceutically acceptable saltthereof, wherein: R* is selected from hydrogen, C1-C¢-alkyl, halo-C)-Co-alkyl, C1-Co-alkyl-NH-Ci-Co- alkyl-, C3-C1o-cycloalkyl, and R*°-O-C1-C¢-alkyl, R?> is hydrogen; and R* is selected from hydrogen, C1-Co-alkyl, halo-C-Cs-alkyl, and phenyl; or 15 R* and R”®, taken together with the carbon atom to which they are attached, form a C3-Co- cycloalkyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, C1-C¢-alkyl, halo-C)-Co-alkyl, C1-Co-alkyl-NH-Ci-Co- 20 alkyl-, Ci-Ce-alkoxy-Ci-Ce-alkyl, and halo-C)-Ce-alkoxy-C1-Ce-alkyl; and R?’ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH3N-CH>-, 25 hydroxymethyl, methoxymethyl, phenoxymethyl, CHF2-O-CHp2-, CF3-O-CH2-, and cyclopropyl; andR?? is hydrogen; or R* and R”°, taken together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl. 30 In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: WO 2025 / 012296 PCT / EP2024 / 069422 -17- R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH3N-CH>-, methoxymethyl, CHF2-O-CH2-, and CF3-O-CH?2-; and R?’ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined 5 herein, or a pharmaceutically acceptable salt thereof, wherein: R* is Ci-Co-alkyl; and R?’ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 10 R** is methyl; and R?’ is hydrogen. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceuticallyacceptable salt thereof, wherein R? is selected from C1-C¢-alkyl and halo- Ci-Co-alkyl. 15 In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R? is selected from methyl and CHF». In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R? is C1-Co-alkyl. In a particularly preferred embodiment, the present invention provides a compound of formula 20 (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R? is methyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, halogen, hydroxy, C:-Ce-alkyl, 5- to 14-membered heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is 25 optionally substituted with 1 substituentselected from halogen and hydroxy-C1-Ce- alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl; or WO 2025 / 012296 PCT / EP2024 / 069422 -18- R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Co- cycloalkyl; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- 5 Cio-cycloalkyl or oxo; R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Co-C10-aryl; wherein said 5- to 14-membered heteroaryl, and C6-Cio-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; 10 R® is hydrogen; and R’ is selected from hydrogen, C1-C¢-alkyl, halo-Ci-Ce-alkyl, and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides acompound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 15 R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4- triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or 20 R* and R®, taken together with the carbon atom to which they are attached, form a cyclopropyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a cyclopropyl; R** and R°® are each independently selected from hydrogen and methyl; or 25 R** and R°°, taken together with the carbon atom to which they are attached, form a cyclopropyl or oxo; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl, andphenyl are substituted with 1-3 substituents independently 30 selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; R° is hydrogen; and R’ is selected from hydrogen, methyl, CHF2, CF3, and imidazolyl. WO 2025 / 012296 PCT / EP2024 / 069422 -19- In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, halogen, hydroxy, C:-Ce-alkyl, 5- to 14-membered heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is 5 optionally substituted with 1 substituent selected from halogen and hydroxy-C1-Ce- alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl; or 10 R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Co- cycloalkyl; R** and R°® are each independently selected from hydrogen andC1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; 15 R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Co-C10-aryl; wherein said 5- to 14-membered heteroaryl, and C6-Cio-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and 20 R’ _ is selected from hydrogen, Ci-Cs-alkyl, halo-Ci-Ce-alkyl, and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, halogen, hydroxy, C:-Ce-alkyl, 5- to 14-membered 25 heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxy-C1-Ce- alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R*®, takentogether with the carbon atom to which they are attached, form a C3- 30 Cyo-cycloalkyl; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; WO 2025 / 012296 PCT / EP2024 / 069422 -20- R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Co-C10-aryl; wherein said 5- to 14-membered heteroaryl, and C6-Cio-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; 5 R® is hydrogen; and R’ _ is selected from hydrogen, halo-C-C¢-alkyl, and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4- 10 triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl,1,2,4-triazolyl, and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or R* and R®, taken together with the carbon atom to which they are attached, form a 15 cyclopropyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a cyclopropyl; R** and R°® are each independently selected from hydrogen and methyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a 20 cyclopropyl; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independently selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; 25 R® is hydrogen; and R’ is selected from hydrogen, methyl, CHF2, CF3, and imidazolyl. In one embodiment, the present inventionprovides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4- 30 triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or WO 2025 / 012296 PCT / EP2024 / 069422 -2]- R* and R*®, taken together with the carbon atom to which they are attached, form a cyclopropyl; R** and R°® are each independently selected from hydrogen and methyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a 5 cyclopropyl; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independentlyselected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; 10 R® is hydrogen; and R’ is selected from hydrogen, CF3, and imidazolyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, halogen, and Ci-Co-alky]; 15 R* is selected from hydrogen and halogen; R* is hydrogen; R° is hydrogen; R® is selected from hydrogen and 5- to 14-membered heteroaryl; wherein said 5- to 14- membered heteroaryl is substituted with 1 substituent selected from halogen, Ci-Ce- 20 alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and R’ _ is selected from hydrogen, halo-Ci-Cs-alkyl, and 5- to 14-membered heteroaryl. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 25 R* is selected from hydrogen, fluoro, and methy];R* is selected from hydrogen and fluoro; R™ is hydrogen; R°’ is hydrogen; R® is selected from hydrogen, pyridyl, and pyrazolyl; wherein said pyridyl and pyrazolyl 30 are substituted with 1 substituent selected from bromo, methyl, cyclopropyl, and pyridyl; R° is hydrogen; and R’ _ is selected from hydrogen, CF3, and imidazoly]. WO 2025 / 012296 PCT / EP2024 / 069422 -22- In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen and halogen; R* is selected from hydrogen and halogen; 5 R* is hydrogen; R° is hydrogen; R® is selected from hydrogen and 5- to 6-membered heteroaryl; wherein said 5- to 6- membered heteroaryl is substituted with 1 halogen substituent; R° is hydrogen; and 10 R’ is hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R** and R®are each independently selected from hydrogen and halogen. In a particularly preferred embodiment, the present invention provides a compound of formula 15 (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R** and R°° are both hydrogen. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R® is selected from hydrogen and 5- to 6-membered heteroaryl; wherein said 5- to 6- 20 membered heteroaryl is substituted with 1 halogen substituent; and R° is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R’ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula 25 (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen and fluoro; R*is selected from hydrogen and fluoro; R* is hydrogen; R° is hydrogen; 30 R® is selected from hydrogen and bromopyridyl; R° is hydrogen; and WO 2025 / 012296 PCT / EP2024 / 069422 -23 - R’ _ is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein R“ and R* are each independently selected from hydrogen and fluoro. 5 Ina particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: R® is selected from hydrogen and bromopyridyl; and R° is hydrogen. In a particularly preferred embodiment, the present invention provides a compound of formula 10 (1)as defined herein, or a pharmaceutically acceptable salt thereof, wherein the group 4b R™ Ri R pe F F 0 0 7 R” os RR” is ; In one embodiment, the present invention provides a compound of formula (I) as defined herein, or apharmaceutically acceptable salt thereof, wherein: U _ isselected from O, S, and NRY; 15 V___isacovalent bond or CHR’; RY is cyano; and RY is halo-Ci-Ce-alkyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 20 U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: RY is cyano; and RY is CFs. In a particularly preferred embodiment, the present invention provides a compound of formula 25 (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein U is O and V is a covalent bond, represented by Formula (Ia): WO 2025 / 012296 PCT / EP2024 / 069422 -24- Rib R°? Ri’ 5b RA Ro R RX JL 9 x ant bey NoveZ OR R pe (Ia) wherein X, Y, Z, and R! to R’ are as defined herein. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 5 (i) Xand Y are CH and Z is CR”; or (ii) X andZ are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: 10 A is selected from 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, phenyl, and C3-C¢-cycloalkyl; L is selected from a covalent bond, -CH2—, and -NR!-: R” is hydrogen; 15 RY is cyano; RY is halo-C1-Co-alky1; R“ is selected from hydrogen and C1-Co-alky]; R! _ is selected from hydrogen, halogen, cyano, C1-Ce-alkyl, C2-Co-alkynyl, halo-C1-Ce- R'2 \y alkyl, hydroxy-C1-Ce-alkyl, Ci-Ce-alkoxy, and a group il ; 20 R'* is selected from hydrogen, halogen, C1-C6-alkyl, and halo-Ci-Ce-alkyl; R* is selected from hydrogen, C1-C¢-alkyl, halo-C)-Co-alkyl, C1-Co-alkyl-NH-Ci-Co- alkyl-, C3-Cio-cycloalkyl, phenyl-Ci-Co-alkyl, and R?°-O-C1-Ce-alkyl; wherein said phenyl is optionally substituted with 1 halogen substituent; R?> is hydrogen; and 25 R* is selectedfrom hydrogen, C1-C¢-alkyl, halo-C1-Ce-alkyl, and phenyl; wherein said phenyl is optionally substituted with 1 halogen substituent; or WO 2025 / 012296 PCT / EP2024 / 069422 -25- R* and R”°, taken together with the carbon atom to which they are attached, form a C3-Co- cycloalkyl; R? is selected from C1-C6-alkyl and halo-C1-Co-alkyl; R* is selected from hydrogen, halogen, hydroxy, C:-Ce-alkyl, 5- to 14-membered 5 heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxy-C1-Ce- alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- 10 Cio-cycloalkyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Co- cycloalkyl; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they areattached, form a C3- 15 Cio-cycloalkyl or oxo; R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Co-C10-aryl; wherein said 5- to 14-membered heteroaryl, and C6-Cio-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; 20 R® is hydrogen; and R’ is selected from hydrogen, C1-C¢-alkyl, halo-Ci-Ce-alkyl, and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 25 (i) Xand Y are CH and Z is CR”; or (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: 30 A is selected from azetidine, tetrahydrofurane, tetrahydropyrane, pyrrolidine, pyrazole, phenyl, pyridyl, and cyclopropyl; L is selected from a covalent bond, -CH2—, and -NR!-: R” is hydrogen; WO 2025 / 012296 PCT / EP2024 / 069422 - 26 -RY is cyano; RY is CF3; R“ _ is selected from hydrogen and methy]; R! _ is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, prop-1-ynyl, R' L 5 hydroxymethyl, CHF2, methoxy, and a group Coy ¥ R!* is selected from hydrogen, chloro, methyl, and and CFs; R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH2CHF2, CH3N-CH>-, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethy]l, fluorophenylethyl, CHF2-O-CHo-, CF3-O-CH2-, and cyclopropyl; and 10 R?? is hydrogen; or R* and R”°, taken together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl; R? is selected from methyl and CHF>; R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4- 15 triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or R* andR®, taken together with the carbon atom to which they are attached, form a 20 cyclopropyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a cyclopropyl; R** and R°® are each independently selected from hydrogen and methyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a 25 cyclopropyl or oxo; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independently selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; 30 R® is hydrogen; and R’ is selected from hydrogen, methyl, CHF2, CF3, and imidazolyl. WO 2025 / 012296 PCT / EP2024 / 069422 -27- In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or (ii) Xand Z are CH and Y is N; or 5 (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: A is selected from 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl comprising 1 to 3 10 heteroatoms selected from N, O, and S, phenyl, and C3-C¢-cycloalkyl; L ___ isselected from a covalent bond and —NR‘-; R” is hydrogen; RY is cyano; RY is halo-C1-Co-alky1; 15 R! is selected from hydrogen, halogen, cyano, Ci-C¢-alkyl, halo-C1-Ce-alkyl, hydroxy- R'2 \y C1-Ce-alkyl, Ci-Ce-alkoxy, and a group il ; R!* is selected from hydrogen, halogen, and Ci-Co-alky]; R* is selected from hydrogen, C1-C¢-alkyl, halo-C)-Co-alkyl, C1-Co-alkyl-NH-Ci-Co- alkyl-, C3-C1o-cycloalkyl, and R*°-O-C1-C¢-alkyl, 20 Ris hydrogen; and R* is selected from hydrogen, C1-Co-alkyl, halo-C-Cs-alkyl, and phenyl; or R* and R”°, taken together with the carbon atom to which they are attached, form a C3-Co- cycloalkyl; R? is Ci-Co-alkyl;25 R* is selected from hydrogen, halogen, hydroxy, C:-Ce-alkyl, 5- to 14-membered heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxy-C1-Ce- alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or 30 R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cio-cycloalkyl; or WO 2025 / 012296 PCT / EP2024 / 069422 -28 - R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Co- cycloalkyl; R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- 5 Cyo-cycloalkyl; R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Co-C10-aryl; wherein said 5- to 14-membered heteroaryl, and C6-Cio-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 5- to14-membered heteroaryl; 10 R® is hydrogen; and R’ is selected from hydrogen, C1-C¢-alkyl, halo-Ci-Ce-alkyl, and 5- to 14-membered heteroaryl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 15 (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: 20 A is selected from azetidine, pyrrolidine, pyrazole, phenyl, and cyclopropyl; L ___ isselected from a covalent bond and —NR‘-; R” is hydrogen; RY is cyano; RY is CF3; 25 R! is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, hydroxymethyl, R'2 L CHF2, methoxy, and a group il Y i R!* is selected from hydrogen, chloro, and methy]; R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH3N-CH>-, hydroxymethyl, methoxymethyl, phenoxymethyl, CHF2-O-CH2-, CF3-O-CH2-, and 30 cyclopropyl; and R?? is hydrogen; or WO2025 / 012296 PCT / EP2024 / 069422 -29 - R* and R”®, taken together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl; R? is methyl; R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4- 5 triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a 10 cyclopropyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a cyclopropyl; R** and R°® are each independently selected from hydrogen and methyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a 15 cyclopropyl; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl,pyridyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independently selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; 20 R® is hydrogen; and R’ is selected from hydrogen, methyl, CHF2, CF3, and imidazolyl. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or 25 (ii) X and Z are CH and Y is N; Us isO; Visa covalent bond; R! is selected from hydrogen, halogen, and Ci-Co-alky]; R* is Ci-Co-alkyl; and 30 R?’ is hydrogen; R? is Ci-Co-alkyl; R* is selected from hydrogen, halogen, and Ci-Co-alky]; R* is selected from hydrogen and halogen; WO 2025 / 012296 PCT / EP2024 / 069422 -30- R* is hydrogen; R° is hydrogen; R® is selected from hydrogen and 5- to 14-membered heteroaryl; wherein said 5- to 14- membered heteroaryl is substituted with 1 substituent selected from halogen, Ci-Ce- 5 alkyl,C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and R’ _ is selected from hydrogen, halo-Ci-Cs-alkyl, and 5- to 14-membered heteroaryl. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 10 (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; Us isO; Visa covalent bond; R! is selected from hydrogen, fluoro, and methy]; 15 R** is methyl; and R?’ is hydrogen; R? is methyl; R* is selected from hydrogen, fluoro, and methy]; R* is selected from hydrogen and fluoro; 20 R* is hydrogen; R° is hydrogen; R® is selected from hydrogen, pyridyl, and pyrazolyl; wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from bromo, methyl, cyclopropyl, and pyridyl; 25 R® is hydrogen; and R’ _ is selected from hydrogen, CF3, and imidazoly]. In one preferred embodiment, the present invention provides a compound of formula (I) as definedherein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or 30 (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: WO 2025 / 012296 PCT / EP2024 / 069422 -31- RY is cyano; and RY is halo-Ci-Ce-alkyl. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: 5 (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: 10 RY is cyano; and RY is CF3. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or 15 (ii) X and Z are CH and Y is N; U — isO; and Vis acovalent bond. In one embodiment, the present invention provides a compound of formula (I) as defined herein, ora pharmaceutically acceptable salt thereof, wherein: 20 X isCHorN; R! is selected from hydrogen, halogen, cyano, C1-Co-alkyl, and C3-Ci0-cycloalkyl; R* is selected from hydrogen, C1-C¢-alkyl, halo-C)-Co-alkyl, C1-Co-alkyl-NH-Ci-Co- alkyl-, Ci-Ce-alkoxy-C1-Ce-alkyl, and halo-C)-Ce-alkoxy-C1-Ce-alkyl; R?’ is hydrogen; 25 R’ is Ci-Ce-alkyl; R* is selected from hydrogen, halogen, hydroxy, C:-Ce-alkyl, 5- to 14-membered heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is optionally substituted with 1 substituent selected from halogen and hydroxy-C1-Ce- alkyl; and 30 R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R*®, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; WO 2025 / 012296 PCT / EP2024 / 069422 -32- R** and R°® are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°®, taken together with the carbon atom to which they are attached, form a C3- Cyo-cycloalkyl; R® is selected fromhydrogen, 5- to 14-membered heteroaryl, and Co-C10-aryl; wherein 5 said 5- to 14-membered heteroaryl, and C6-Cio-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and R’ _ is selected from hydrogen, halo-C-C¢-alkyl, and 5- to 14-membered heteroaryl. 10 In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: X isCHorN; R! _ is selected from hydrogen, fluoro, chloro, cyano, methyl, and cyclopropyl; R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH3N-CH>-, 15 methoxymethyl, CHF2-O-CH)2-, and CF3-O-CH?2-; R?’ is hydrogen; R? is methyl; R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4- triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl 20 is optionally substituted with 1 substituent selectedfrom chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or R* and R®, taken together with the carbon atom to which they are attached, form a cyclopropyl; 25 R** and R°® are each independently selected from hydrogen and methyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a cyclopropyl; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 30 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independently selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; R° is hydrogen; and R’ _ is selected from hydrogen, CF3, and imidazoly]. WO 2025 / 012296 PCT / EP2024 / 069422 -33- In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: xX is CH; R! is hydrogen; 5 R* isCi-Co-alkyl; and R?’ is hydrogen; R? is Ci-Co-alkyl; R* is selected from hydrogen, halogen, and Ci-Co-alky]; R* is selected from hydrogen and halogen; 10 R* is hydrogen; R° is hydrogen; R® is selected from hydrogen and 5- to 14-membered heteroaryl; wherein said 5- to 14- membered heteroaryl is substituted with 1 substituent selected from halogen, Ci-Ce- alkyl, C3-Cio-cycloalkyl, and 5- to 14-membered heteroaryl; 15 R® is hydrogen; and R’ is selected from hydrogen, halo-C-C¢-alkyl, and 5- to 14-membered heteroaryl. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein: xX is CH; 20 R! is hydrogen; R* is methyl; and R?’ is hydrogen; R? is methyl; R* is selected from hydrogen, fluoro, and methy]; 25 R* is selected from hydrogen and fluoro; R* is hydrogen; R° is hydrogen; R® is selected from hydrogen, pyridyl, and pyrazolyl; wherein said pyridyl and pyrazolyl are substitutedwith 1 substituent selected from bromo, methyl, cyclopropyl, and 30 pyridyl; R° is hydrogen; and R’ _ is selected from hydrogen, CF3, and imidazoly]. WO 2025 / 012296 PCT / EP2024 / 069422 -34- In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 1-methyl-1-[(1S)-1-(4-pyridyl)ethy]]-3-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)urea; 5 1-[(3-chloro-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-fluoro-4-pyridyl)methy]]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-(4-pyridylmethyl)urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 10 3-[(3R)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]Jurea;3-[(3R)-4,4-difluorotetrahydrofuran-3-y1]-1-methyl-1-[(1 R)-1-(4-pyridyl)propylJurea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethy]]urea; 15 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl ]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethy]]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 20 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethy]]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl ]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 25 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethylurea; 3-(4-benzoyltetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethy]]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethy1]-3-[(3R)-3-(trifluoromethy])tetrahydrofuran-3-yl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethy1]-3-[(3 S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 30 =: 1-methyl-1-[(1S)-1-(4-pyridylethyl]-3-[(@R)-3-(trifluoromethy!)tetrahydrofuran-3-yl]urea; 1-methyl-1-[(1S)-1-(4-pyridyl)ethy1]-3-[(3 S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methy] urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 1-[(3-bromo-4-pyridyl)methy]]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; WO 2025 / 012296 PCT / EP2024 / 069422 -35- 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl urea; 5 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea;3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 10 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[[3-(hydroxymethyl)-4-pyridyl]methyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridyl)ethyl]urea; 15 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]Jurea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridylethy]]urea; 1-[(3-cyclopropyl-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea;1-[(3-bromo-4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 20 -1-[(3-bromo-4-pyridyl)methy]]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(azetidin-1-yl)-4-pyridyl]methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[2-methoxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3 -yl)-1-[(3-methoxy-4-pyridyl)methy] ]-1-methyl-urea; 25 1-[1-(3-chloro-4-pyridyl)ethy1]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-pyrrolidin-1-yl-4-pyridyl)methy]]urea; 1-[(S)-cyclopropyl(4-pyridyl)methy1]-3-[(3 S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(S)-cyclopropyl(4-pyridyl)methy1]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 30~—-1-[(R)-cyclopropyl(4-pyridyl)methy!]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 3-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-y1]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 36- 3-[(28,3R)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-y1]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 5 1-[(1R)-1-(3-chloro-4-pyridyl)ethy!]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea;1-[[3-(3-chloroanilino)-4-pyridyl]methy1]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- 10 urea; 1-[[3-(3-chloroanilino)-4-pyridyl]methy1]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 3-[(3S)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl urea; 3-[(3R)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]Jurea; 15 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethy]]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl ]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl urea; 1-methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridylethyl]Jurea; 20 1-methyl-3-[(1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridylethyl]Jurea;1-methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridylethyl]Jurea; 1-methyl-3-[(18,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridylNethy]]urea; 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 25 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl- urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]Jurea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(1 H-pyrazol-5-yl)-4-pyridyl]methy]]urea; 30 = 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea;3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[3-(difluoromethyl)tetrahydrofuran-3 -yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea; WO 2025 / 012296 PCT / EP2024 / 069422 -37- 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridylethy]]thiourea; 3-(4,4-difluorotetrahydrofuran-3-y1)-1-methyl-1-[[3-(3-methyl-1H-pyrazol-5-yl)-4- 5 pyridyl ]methyl urea; 2-cyano-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridylethyl]guanidine; 1-methyl-3-(5-oxotetrahydrofuran-3-yl)-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4- pyridyl ]methyl urea; 10 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4- pyridyl ]methyl urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4- pyridyl ]methyl urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methy]]-4- 15 pyridyl ]methyl urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[[3-(4-pyridyl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[[3-(3-pyridyl)-4-pyridyl]methyl]urea; 1-[[3-(4-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 20 -1-[[3-(2-chloropheny1)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl- urea; 1-[[3-(3-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 1-[2-(3-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 25 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-prop-1-ynyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(2-pyridyl)-4-pyridyl]methyl]urea; 1-[2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 30 = 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4- pyridyl ]methyl urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4- pyridyl ]methyl urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 38 - 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[4-(trifluoromethyl)pheny]]-4- pyridyl ]methyl urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridy])ethyl]-1-methyl- urea; 5 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridy])ethyl]-1-methyl- urea;3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- 10 urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridy])ethyl]-1-methyl- urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea]; 15 [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- 20 urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3 yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea; 25 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea];1-[(1S)-1-(3-bromo-4-pyridyl)ethy!]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-bromo-4-pyridyl)ethy!]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridy])ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 30 ~—-1-[(1R)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3 S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridy1)ethyl]-3-[(3 S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridy|)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; WO 2025 / 012296 PCT / EP2024 / 069422 -39- 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridylethyl]-3-[(3 S)-4,4-difluorotetrahydrofuran-3-y1]-1- methyl-urea; 5 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1- methyl-urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1 R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1- 10 methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1- methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl- urea; 15 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[@GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[GS)-4,4-difluorotetrahydrofuran-3 -yl]-1-methyl- 20 urea; 1-(difluoromethy1)-3-(4,4-difluorotetrahydrofuran-3-yl)-1-(4-pyridylmethyl)urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridylethyl]-1-methyl-urea];[3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 25 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethy1]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-@-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethy1]-1-methyl-urea]; 30 ~—- [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethy1]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-@-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-[(1R)-1-(3-ethyl-4-pyridylethyl]-1-methyl-urea]; and WO 2025 / 012296 PCT / EP2024 / 069422 - 40 -3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2,2,2-trifluoro-1-(4-pyridyl)ethyl]urea]. In one embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from: 5 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-tetrahydrofuran-3-yl urea; 1-methyl-3-[(3RS, 4RS)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridylethyl]urea; 1-methyl-3-[(3RS, 4SR)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridylethyl]urea; 1-methyl-1-[(1S)-1-(4-pyridylethyl]-3-[(3RS)-3-(trifluoromethyl)tetrahydrofuran-3- yljurea; 10 3-[(3RS)-3-(1 H-imidazol-2-yl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]urea; 1-methyl-3-[(3RS)-3-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]-1-[(1S)-1-(4- pyridyl)ethyl]urea; 3-[(2RS,3SR)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 15 pyridyl)ethy]]urea; 1-methyl-1-[(1S)-1-(4-pyridy)ethyl]-3-[(2RS,3 SR)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2RS,3SR)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3 -yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]urea; 20 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(28,3R)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 25 pyridyl)ethy]]urea; 3-[(2R,3S)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]urea; 1-methyl-1-[(1S)-1-(4-pyridylethy]]-3-[(2R,3S)-2-[5-(3-pyridyl)-3- pyridyl]tetrahydrofuran-3-yl]urea; 30 1-methyl-1-[(1S)-1-(4-pyridylethy]]-3-[(28,3R)-2-[5-(3-pyridyl)-3- pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2R,3S)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethylJurea; and WO2025 / 012296 PCT / EP2024 / 069422 -4] - 3-[(28,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]urea. In a preferred embodiment, the present invention provides a compound of formula (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 5 selected from: 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methy]]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethy] urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 10 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethy])urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethylurea;3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methy] urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 15 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridylethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethylJurea; and 20 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (1) is 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea. In a particularly preferred embodiment, the present invention provides a compound of formula 25 (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of 30 formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea. WO 2025 / 012296 PCT / EP2024 / 069422 -42- In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- ylethyl]urea. 5 Ina particularly preferredembodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- ylethyl]urea. In a particularly preferred embodiment, the present invention provides a compound of formula 10 (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (1) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea. 15 Ina particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, whereinsaid compound of formula (I) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4- pyridyl)methyl]urea. In a particularly preferred embodiment, the present invention provides a compound of formula 20 (I) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4- pyridyl)methyl]urea. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of 25 formula (1) is 3-[(3S)-4,4-difluorotetrahydrofuran-3 -yl]-1-[(1S)-1-(3-fluoro-4-pyridylethyl]-1- methyl-urea. In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(@-fluoro-4-pyridyl)ethyl]-1-30. ~=methyl-urea. WO 2025 / 012296 PCT / EP2024 / 069422 - 43 - In a particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (1) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(@-fluoro-4-pyridyl)ethyl]-1- methyl-urea. 5 Ina particularly preferred embodiment, the present invention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (1) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethy]]-1- methyl-urea. In a particularly preferred embodiment, the present invention provides a compound of formula 10 (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]urea. In a particularly preferred embodiment, the presentinvention provides a compound of formula (1) as defined herein, or a pharmaceutically acceptable salt thereof, wherein said compound of 15 formula (1) is 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]urea. In a particular embodiment, the present invention provides pharmaceutically acceptable salts of the compounds according to formula (1) as described herein. In a further particular embodiment, the present invention provides compounds according to formula (I) as described herein as free 20 bases. In some embodiments, the compounds of formula (1) are isotopically-labeled by having one or more atoms therein replaced by an atom having a different atomic mass or mass number. Such isotopically-labeled (1.¢e., radiolabeled) compounds of formula (1) are considered to be within the scope of this disclosure. Examples of isotopes that can be incorporated into the compounds of 25 formula (1) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, 7H, 7H, "C, °C, 4c, 3N, PN, 0, 170, BO 3p Bp sR 36C] 131 and '°I, respectively. Certain isotopically-labeled compounds of formula (1), for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. 7H, and carbon-14, ie., 30 MC, are particularly useful for this purpose in view of their ease of incorporation and ready WO 2025 / 012296 PCT / EP2024 / 069422 -44- means of detection. For example, a compound of formula (I) can be enriched with 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99 percent of a given isotope. Substitution with heavier isotopes such as deuterium, i.e. 7H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or 5 reduced dosage requirements. Thus, in one embodiment, the present invention provides compounds of formula (1) as described herein,wherein one or more hydrogen atoms are replaced by deuterium, preferably wherein 1-4 hydrogen atoms are replaced by deuterium, more prefereably wherein 1-3 hydrogen atoms are replaced by deuterium. Substitution with positron emitting isotopes, such as 'C, '8F, !°O and '3N, can be useful in 10 Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non- labeled reagent previously employed. 15 Processes of Manufacturing The preparation of compounds of formula (1) of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses of the invention are shown in the following general schemes. The skills required for carrying out the reaction andpurification of the resulting products are known to those persons skilled in the art. The substituents and indices used in the 20 following description of the processes have the significance given herein, unless indicated to the contrary. If one of the starting materials, intermediates or compounds of formula (I) contain one or more functional groups which are not stable or are reactive under the reaction conditions of one or more reaction steps, appropriate protective groups (as described e.g., in “Protective Groups in 25 Organic Chemistry” by T. W. Greene and P. G. M. Wutts, 5th Ed., 2014, John Wiley & Sons, N.Y.) can be introduced before the critical step applying methods well known in the art. Such protective groups can be removed at a later stage of the synthesis using standard methods described in the literature. If starting materials or intermediates contain stereogenic centers, compounds of formula (I) can 30 be obtained as mixtures of diastereomers or enantiomers, which can beseparated by methods WO 2025 / 012296 PCT / EP2024 / 069422 - 45 - well known in the art e.g., chiral HPLC, chiral SFC or chiral crystallization. Racemic compounds can e.g., be separated into their antipodes via diastereomeric salts by crystallization with optically pure acids or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbent or a chiral eluent. It is equally possible to separate starting materials and 5 intermediates containing stereogenic centers to afford diastereomerically / enantiomerically enriched starting materials and intermediates. Using such diastereomerically / enantiomerically enriched starting materials and intermediates in the synthesis of compounds of formula (I) will typically lead to the respective diastereomerically / enantiomerically enriched compounds of formula (1). 10 A person skilled in the art will acknowledge that in the synthesis of compounds of formula (1) - insofar not desired otherwise - an “orthogonal protectiongroup strategy” will be applied, allowing the cleavage of several protective groups one at a time each without affecting other protective groups in the molecule. The principle of orthogonal protection is well known in the art and has also been described in literature (e.g. Barany and R. B. Merrifield, . Am. Chem. Soc. 15 1977, 99, 7363; H. Waldmann et al., Angew. Chem. Int. Ed. Engl. 1996, 35, 2056). A person skilled in the art will acknowledge that the sequence of reactions may be varied depending on reactivity and nature of the intermediates. In more detail, the compounds of formula (I) can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions 20 for the individual reaction steps are known to a person skilled in the art. Also, for reaction conditions described in literature affecting the described reactions see for example: Comprehensive Organic Transformations: A Guide to Functional GroupPreparations, 2nd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 1999). It was found convenient to carry out the reactions in the presence or absence of a solvent. There is no particular 25 restriction on the nature of the solvent to be employed, provided that it has no adverse effect on the reaction or the reagents involved and that it can dissolve the reagents, at least to some extent. The described reactions can take place over a wide range of temperatures, and the precise reaction temperature is not critical to the invention. It is convenient to carry out the described reactions in a temperature range between -78 °C to reflux. The time required for the reaction may 30 also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents. However, a period of from 0.5 hours to several days will usually suffice to yield the described intermediates and compounds. The reaction sequence is not limited to the one WO 2025 / 012296PCT / EP2024 / 069422 - 46 - displayed in the schemes, however, depending on the starting materials and their respective reactivity, the sequence of reaction steps can be freely altered. If starting materials or intermediates are not commercially available or their synthesis not described in literature, they can be prepared in analogy to existing procedures for close 5 analogues or as outlined in the experimental section. The following abbreviations are used in the present text: °C = degree Celsius; Boc2zO = di-fert-butyl dicarbonate; CataCXium Pd G4 = [di(adamantan-1- yl)(butyl)phosphine](methanesulfonato-«O)[2'-(methylamino)-2-biphenylyl]palladium; CDT = 1,1'-Carbonyl-di-(1,2,4-triazole); CH3CN = acetonitrile; CHCl3 = chloroform; Cs2CO3 = cesium 10 carbonate; Cul = copper iodide; DCE = dichloroethane; DCM = dichloromethane; DIPEA = N,N- Diisopropylethylamine; DMF = N,N-dimethylformamide; ESI = electrospray ionization; EtzO = diethylether; EtOAc = ethyl acetate; EtOH = ethanol; FC = flashchromatography; h = hour(s); H2 = hydrogen; H2O = water; HCl = hydrogen chloride; HCOOH = formic acid; HPLC = high performance liquid chromatography; IPA = propan-2-ol; i-PrMgCl-LiCl = isopropylmagnesitum 15 chloride lithtum chloride complex; K2CO3 = potassium carbonate, KHMDS = potassium bis(trimethylsilyl)amide; KH2PO4 = potassium dihydrogen phosphate; KI = potassium idodide; LiAIH, = lithtum aluminium hydride; LiCl = lithium chloride; M = molar; MeMgBr = methylmagnesium bromide; MeNH2 = methylamine; MeOH = methanol; 2-Me-TFH = 2- methyltetrahydrofuran; mg = milligram(s); MgSO4 = magnesium sulfate; min = minute(s); mL = 20 milliliter; mm = millimeter(s); mmHg = millimeter(s) of mercury; MS = mass spectrometry; Ms2O = methanesulfonic anhydride; MTBE = 2-methoxy-2-methylpropane; m / z = mass-to-charge ratio; NaBH3CN = sodium cyanoborohydride; NaBH4 = sodium borohydride; NaHSO4 = sodium hydrogen sulfate, NaNOz = sodium nitrite, NaOAc = sodium acetate; NazSOx4 = sodium sulfate; NH,Cl =ammonium chloride; nm = nanometer(s); PE = petroleum ether; Pd / C = palladium on 25 carbon; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium; Pd(OAc)2 = Palladium(I]) acetate; (PPh3)2PdClz2:DCM = bis(triphenylphosphine)palladium chloride dichloromethane solvate; ppm = part(s) per million) RP = reverse phase; RuPhos = 2-dicyclohexylphosphino-2',6'- diisopropoxybiphenyl; SFC = supercritical fluid chromatography; SiOz = silicon dioxide; SOCI2 = thionyl chloride; ‘BuOH = ¢ert-butanol; TEA = trimethylamine; THF = tetrahydrofuran; 30 © Ti(O'Pr)4 = Titanium isopropoxide; tr = retention time; Xantphos = (9,9-dimethyl-9H4-xanthene- 4,5-diyl)bis(diphenylphosphane); wL = microliter(s), um = micrometer(s). WO 2025 / 012296 PCT / EP2024 / 069422 -47- The present compounds of general formula (I) where U= O or S and V = covalent bond or C(R™)2 can be prepared starting from an intermediate of formula 1 as shown in Scheme 1. Intermediate 1 can be activated with a coupling agent such as CDT (U = O) or1,1'-thiocarbonyldiimidazole (U = S) in the presence of a base (e.g. TEA, DIPEA) in a solvent such as DMF, DCM or CH3CN to 5 generate the activated intermediate 2 in situ. Addition of intermediate 3 to the reaction mixture generates compounds of general formula (I). In some instances, intermediate 2 can be isolated, and then converted to the corresponding urea using the above-mentioned reaction conditions. Furthermore, the order of addition can be interconverted and in some instances, intermediates of formula 3 can be activated first, and amines of formula 1 added in a second time to the reaction 10 mixture. A person skilled in the art will recognize that when amines of formula 1 are not commercially available, they can be prepared via a Curtius rearrangement from the corresponding carboxylic acids, using standard reaction conditions. 1 RS R® R\_x H 3 Ri am —— ne — es oem 1 2 0 Scheme 1 15 The building blocks of general formula 1 are commercially available or can be prepared viamethods known to the person skilled in the art. Building blocks of general formula 3 can be obtained commercially or can be prepared via methods known to the person skilled in the art (e.g. reductive amination from the corresponding ketone or aldehyde and amine or using Ellman-type chemistry followed by a reduction or an alkylation step). 20 Alternatively, amines of general formula 3 where R' = CH2.OH, X = C, R™, R” = hydrogen, C1- Co-alkyl and R? = Ci-C¢-alkyl or C3-Cio-cycloalkyl, depicted as compound 4 in Scheme 2, can be prepared starting from suitably protected aryl bromide 5. Ester 6 can be prepared via carbonylation of bromide 5 using a palladium catalyst in the presence of a base such as TEA and MeOH, in a carbon monoxide atmosphere. Hydroxymethyl] intermediate 7 can be prepared from ester 6 using 25 standard reaction conditions such as LiAlHg in a polar aprotic solvent such as THF. Deprotection of the amine using conditions known to a person skilled in the art affords aminesof general formula 4. WO 2025 / 012296 PCT / EP2024 / 069422 - 48 - \, HO Bra? Re Ox ne R2 HO RR? R22 RD Ao? _CO , 2B n-PO _reduction AX Seprotection = “7 ~ nom 7 Oe Nez OR Ne LZ OR Na ZR Nay OR Sy- Sy- Sy- 5 6 7 4 Scheme 2 Alternatively, amines of general formula 3 where L = covalent bond, A = 3- to 14-membered heterocyclyl, R!* =H, halogen, C1-Co-alkyl, X = C, R**, R® = hydrogen, Ci-Ce-alkyl and R? = C- 5 Ce-alkyl or C3-Cio-cycloalkyl, depicted as compound 8 in Scheme 3, can be prepared from suitably protected commercially available bromides 5. Buchwald-Hartwig cross-coupling of bromides 5 with commercially available amines 9 using a Pd-catalyst such as Pd2(dba)3 in the presence of a ligand such as Xantphos and a base such as but no limited to Cs2CO3 at elevated temperatures in a polar aprotic solvent such as 1,4-dioxane followed by deprotection affords amines of general 10 formula 8. A person skilled in the art will recognize that amines 8 can be prepared using alternative methods such asSnAr or Chan-Lam couplings. R'? A Br R22 Ro Oe) 2b ADs R'? NH 1. cross-coupling RR 4 | ls + A 2. deprotection Zo N~ Nw UZ OR —_ | I Y Nw UZ OR Sy 5 9 8 Scheme 3 Alternatively, amines of general formula 3 where L = covalent bond, A = 5- to 14-membered 15 heteroaryl, Cs-Cio-aryl and C3-Cio-cycloalkyl, R!* = H, halogen, C1-Co-alkyl, X = C, R*, R*> = hydrogen, Ci-Co-alkyl and R* = Cy-Ce-alkyl or C3-Cio-cycloalkyl, depicted as compound 10 in Scheme 3, can be prepared from suitably protected commercially available bromides 5. Suzuki- Miyaura cross-coupling of bromides 5 with commercially available potassium trifluoroborates 11 using a Pd-catalyst such as Pd(OAc)2 in the presence of a ligand such as RuPhos or catalytic 20 systems such as CataCXium Pd G4 and a base such as but no limited to KH2PO4 or Cs2COs at elevated temperatures in toluene and water followed by deprotection affords amines of general formula 10. A person skilled in the art will recognize that potassium trifluoroborates 11can be replaced by the corresponding boronic acids or pinacol boronic esters. A person skilled in the art WO 2025 / 012296 PCT / EP2024 / 069422 - 49 - will also recognize that the electrophiles and nucleophiles can be interchanged depending on the substitutents, leading to the same compound 10. R!a Br pa R> KvT eg 2a 426 1a BL . R aR _PG R F 1. cross-coupling Ay 2. deprotection H 5 + pro Z NZ Nw UZ OR ————_—> | 3 Sy Ni UZ OR “yY 5 11 10 Scheme 4 5 Alternatively, amines of general formula 3 where R™* = hydrogen, R* = hydrogen, Ci-C¢-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce6-alkoxy, Ci-Ce-alkyl-NH-Ci-Ce-alkyl-, C3-Cio- cycloalkyl, and R?°-O-C1-Co-alkyl, depicted as compound 12 in Scheme 5, can be prepared from the corresponding commercially available ketone (when R”” = C1-Co-alkyl, halo-C1-Cs-alkyl, Ci- Ce-alkoxy, halo-C1-Ce-alkoxy, Ci-Co-alkyl-NH-C1-Co-alkyl-, C3-Cio-cycloalkyl, and R*°-O-C- 10 Co-alkyl) or aldehydes (when R° = hydrogen) 13. Treatment of 13 with an amine R*NHp (14)in a polar protic solvent such as 2-propanol or EtOH followed by reduction of the in situ generated imine by a reducing agent such as NaBHsg or sodium triacetoxyborohydride affords amines of general formula 12. In some instances, Ti(O'Pr)4 can be added to help imine formation. A person skilled in the art will recognize that ketones of general formula 13 can be prepared using standard 15 chemistry starting from the corresponding bromide (e.g. but not limited to Grignard reaction or Weinreb ketone synthesis). R°? 4. R8NH, (14) , 4 Re Ro AG 2. reducing agent RO Nw ZR 13 12 Scheme 5 Alternatively, amines of general formula 3 where L = NH, A = 3- to 14-membered heterocyclyl, 20 R'*=H, halogen, Ci-Co-alkyl, X = C, R**, R® = hydrogen, C-Co-alkyl and R? = Ci-Co-alkyl or C3-Cio-cycloalkyl, depicted as compound 15 in Scheme 6, can be prepared from suitably protected commercially available bromides 5. Buchwald-Hartwig cross-coupling of suitably protected bromides 5 with commercially availableamines 16 using a Pd-catalyst such as Pd2(dba)3 or WO 2025 / 012296 PCT / EP2024 / 069422 -50- Pd(OAc)2 in the presence of a ligand such as Xantphos or 2,2'-bis(diphenylphosphino)-1, 1'- binaphthyl and a base such as but no limited to Cs2COs3 at elevated temperatures in solvent such as 1,4-dioxane or toluene followed by deprotection affords amines of general formula 15. A person skilled to the art will recognize that amines 15 can be prepared using alternative methods such as 5 SnAr or Chan-Lam couplings. Ria eR 1a __NHp C) RVR? 5 16 ae 15 Scheme 6 Alternatively, amines of general formula 3 where R** = hydrogen, R”? = hydrogen, C1-Co-alkyl, halo-Ci-Ce-alkyl, Ci-Ce-alkoxy, halo-Ci-Ce-alkoxy, C1-Ce-alkyl-NH-Ci-Ce-alkyl-, C3-Cio- 10 cycloalkyl, and R*°-O-C1-C¢-alkyl, depicted as compound 12 in Scheme 7, can be prepared from the corresponding commercially available ketones (when R” = C\-Co-alkyl, halo-C1-Co-alkyl, Ci- Ce-alkoxy, halo-C1-Ce-alkoxy, Ci-Co-alkyl-NH-C1-Co-alkyl-, C3-Cio-cycloalkyl,and R*°-O-C- Co-alkyl) or aldehydes (when R?® = hydrogen) 13. Treatment of building block 13 with a reducing agent such as as NaBHsg or sodium triacetoxyborohydride affords alcohols of general formula 17. 15 Conversion of the alcohol to a better leaving group with e.g. but not limited to MeSO2Cl followed by substitution with an amine 14 in the presence of a base such as DIPEA or TEA gives amines of general formula 12. A person skilled in the art will recognize that when not commercially available, ketones of general formula 13 can be prepared using standard chemistry starting from the corresponding bromide (e.g. but not limited to Grignard reaction or Weinreb ketone synthesis). Re R 4. MeSo,cl , 4 Re Ro A, reducing agent RS Aw 2. R°NH, (14) Aut Nay 22 Nev eZ NZ R 20 13 17 12 Scheme 7 Amines of general formula 1 where V = covalent bond, R** = R* = R** = R*® = R°® = R7= hydrogen, R°® = 5- to 14-membered heteroaryl and Cs-Cio-aryl, depicted as compound 18 in WO 2025 / 012296PCT / EP2024 / 069422 -5]- Scheme 8, can be prepared starting from aldehyde 19. Treatment of aldehyde 19 with methyl-4- chlorobutyrate in THF followed by NaO'Bu affords the corresponding tetrahydrofuran 20. Tetrahydrofuran 20 can be converted to the corresponding amine 18 via a Curtius rearrangement, e.g. using TEA, tert-butanol and diphenylphosphoric azide at 80 °C followed by deprotection. OH ba R™ 5 19 20 18 Scheme 8 Compounds of general formula (1) where U = N-CN, depicted as compound 21 in Scheme 9, can be prepared starting from thiourea 22. Thiourea 22 can be prepared as described in Scheme 1. Methylation of 22 with Mel followed by NH3 in MeOH affords thioethers 23. Treatment of 10 thioethers 23 with cyanamide in the presence of a base such as DIPEA in THF give compounds of general formula 21. N Re Res Rs a i (RR sv RN i - , RR? Le i _ Ne 22 43 Ls pe NyZ OR Ar lee R NyveZ OR aT hea R 22 23 21 Scheme 9 15 Alternatively, amines of general formula 3 where L = CH2 and A =C3-Cjo-cycloalkyl, depicted as compound 24 in Scheme 10, can be prepared from suitably protected commercially available bromides 5. Suzuki-Miyaura cross-coupling of bromides 5 with commercially available pinacol esters 25 using a Pd-catalyst such as Pd(OAc)2 in the presence of a ligand such as RuPhos or catalytic systems such as CataCXium Pd G4 and a base such as but no limited to KH2POs, or 20 Cs2COx3 at elevated temperatures in toluene and water affords alkenes 26. Hydrogenation of alkenes 26 using Pd / C under hydrogen atmosphere in EtOAc gives compounds of general formula 24. If not commercially available, pinacol esters 25 can be prepared as reported by Kovalenko ef al., EJOC 2019, 33, 5624-5635). WO 2025 / 012296 PCT / EP2024 / 069422 -52- Brp2e R? ye a a o2b AX + “CY st D.6 5 deproveation ag, 5 25 26 24 Scheme 10 Alternatively, amines of general formula 3 where R** = hydrogen, depicted as compound 3 in 5 Scheme 11, can be prepared starting from commercially available aldehydes 27.Aldehydes 27 can be treated with a Grignard reagent to give secondary alcohols 17. Alcohols 17 can be treated with SOC) to generate the corresponding chlorides 28. Chlorides 28 can be substituted by amines 14 in the presence of a base such as K2COs, optionally in the presence of an additive such as KI, in a polar solvent such as but not limited to DMF, to give amines of general formula 12. If 10 not commercially available, aldehydes 27 can be prepared from the corresponding heterocycles or halides using methods known to a person skilled in the art. Similarly, alcohols of formula 17 can be converted to other leaving groups such as bromides or mesylates using standard methods. RX i R2MgBr R\ x ie SOC, RX ie eco, “ Ry Me Roy oman Ryo —_ Rye owe woo 1 ie “Y 27 “78 8C a7 “y- 28 . 12 Scheme 11 15 Alternatively, amines of general formula 3 where R™ = hydrogen and R?? = Co-Co-aryl-C1-Co- alkyl and C = heteroaromatic ring optionally substituted with 1-2 halogen substituents, depicted ascompound 29 in Scheme 12, can be prepared starting from homobenzylic aldehyde of general formula 30. Treatment of aldehyde 30 with 4-methylbenzenesulfonohydrazide (31) in MeOH at 60 °C generates compounds of general formula 32. Treatment of 32 with aldehyde 27 in the 20 presence of a base such as Cs2CQ3 in a polar aprotic solvent such as 1,4-dioxane at elevated temperatures gives ketones 33. Condensation of amine 14 with ketone 33 in THF, optionally in the presence of an acid such as acetic acid, followed by reduction of the imine generated in situ (e.g. using but not limited to NaBH3CN), generates amines of general formula 29. WO 2025 / 012296 PCT / EP2024 / 069422 - 53 - cr i © R. x SS H 20 wns i Y ° 1. RONH, (14) H ‘ H Sy 1 -RINH, 1 Cy Om Cuaron 27 ak | So 2. reducing agent ot ) Ne 30 MeOH, 60 °C °° Cs,CO, Nay 4 Nay-Z OR 32 1,4-dioxane, heat 33 29 Scheme 12 Alternatively, amines of general formula 3 where R™* = H and R”? = halo-C-C¢-alkyl, depicted as compound 12 in Scheme 13, can beprepared starting from esters of general formula 34. Esters 34 5 yield alkylation products 35 upon treatment with LDA and a trifluoromethyl sulfonate 36, at -40 °C in THF. Treatment of esters 35 with hydrazine in EtOH at elevated temperatures gives hydrazides 37. Hydrazides 37 give carbamates 38 in a Curtius rearrangement, upon treatment with an acid such as HCl, followed by NaNOz, water, and tBuOH. Carbamates 38 can be alkylated with an alkylating agent R°-X (X = halide) and a base such as but not limited to NaH in a polar aprotic 10 solvent such as THF, giving carbamates 39. Deprotection of 39 gives amines of general formula 12. ob of F : xz TR hydrazine 1 AR > NaNO, H,0 RY? LDA, -40 °C Res EIOH, heat Re Me 3, {BUOH, heat NeeZ OW THE Ny ZO TO 2 HN . 34 . 35 ~ TY" 37 NHe . 4 R? oO Ro 4 Re ReX, ha M1 k bose Ba Ak DCM R\ Xe NZ oH — es a a I Sy Sy- Nw JZ R Y 38 39 12 Scheme 13 Alternatively, amines of general formula 3 where R* = halo-Ci-Co-alkyl can be prepared from 15 benzylic amines40 (Scheme 14). Treatment of amines 40 with (2,5-dioxopyrrolidin-1-yl) formate (41) in THF followed by addition of a base such as TEA gives formamides 42. Treatment of formamides 42 with Lawesson’s reagent, followed by TEA and H20, gives thioformamides 43. Treatment of thioformamides 43 with AgOCF3 gives amines of general formula 3. WO 2025 / 012296 PCT / EP2024 / 069422 -54- e} N (e) ST a Re a4 a2 Re 6 22 Rs 2a Reb 1 1. THF, 0 °C, 1 1.Lawesson's reagent, , RF AgOCF,, 1_R Be 2. TEA, ACN Be A, 2. TEA, H,0, Be AL CHCN ea NeveZ A Ne THE Nay eZ Ny 22 R° 40 42 43 3 Scheme 14 Alternatively, amines of general formula 3 can be prepared starting from commercially available benzylic amines 40 (Scheme 15). Amines 40 can be protected (e.g. but not limited to Boc) using 5 standard conditions, to generate protected amines 44. Alkylation of such amines 44 using a base (e.g. NaH or KHMDS) and a methylating agent R*-X (X = halide) gives tertiary amines 45. Deprotection using standard conditions lead toamines of general formula 3. If not commercially available, benzylic amines 40 can be prepared using techniques known to a person skilled in the art. a Re R2 R> + KHMDS R2 R? ; Re Re» 1 : “O3 y . RV X LH Re protection step Res Me 2. R°X, Bers deprotection i a N Z H Na LZ H THF Na LZ R Sy wN- Y' Y' 10 40 44 45 3 Scheme 15 Alternatively, amines of general formula 3 where R** = hydrogen and R?° = R*°-O-C1-Co-alkyl, depicted as compound 46 in Scheme 16, can be prepared starting from commercially available phenols 47. Treatment of phenols 47 with acetyl bromides 48 and a base such as K2COs3 in a polar 15 aprotic solvent such as MeCN generate ethers 49. Ethers 49 can be converted to amines of general formula 46 via reductive amination, using standard reaction conditions (e.g. NaOAc or TEA as a base and NaNH3CN as reducing agent). . © fe ; fe) 4. R°-NH,, H R 1 (0 pon + sk. base R\ ~~ 2. NaBHICN ae NZ Koso STE Sy7 Ny AZ Nay-Z OR 47 48 Y 49 46 Scheme 16 20 WO 2025 / 012296 PCT / EP2024 / 069422 -55-Alternatively, compounds of general formula (I) where U = O, V = covalent bond, A = 3- to 14- membered heterocyclyl, 5- to 14-membered heteroaryl, or Ce-Cio-aryl, depicted as compound 50 in Scheme 17, can be generated from compounds of general formula 51. Bromides of general formula 51 can be prepared as described in Scheme 1. Suzuki-Miyaura cross-coupling between 5 bromides 51 and commercially available pinacol esters 52 using a catalyst such as cataCXium Pd G4 and a base such as Cs2CO3 in 1,4-dioxane / H20 affords to compounds of general formula 50. A person skilled in the art should recognize that alternative aryl halides could be used for the cross- coupling, such as aryl chlorides or aryl iodides. al Ax IL ney R's =“? cross-couplin hey aw R o~ Ne N“ oo? 1) pling Z~ N ) NyZ OR Ar hes R Neve2 63H Lt pe 51 52 50 10 Scheme 17 Alternatively, compounds of general formula (I) where R! = C2-Co-alkynyl, depicted as compound 53 in Scheme 18, can be prepared from bromides 51. Bromides 51 canbe coupled with alkynes 54 in a Sonogashira cross-coupling using e.g. Cul, bis(triphenylphosphine)palladium(II) chloride, 15 TEA in THF, to give the alkyne-containing compounds of general formula 53. R R Br Rey RN a _ Aa bey Je L 7 AS ane . Pd-cat, base, Cul , Ae NyZ OR AT dee R THF Na 2 i oH Ite pe 51 53 Scheme 18 Alternatively, compounds of general formula (I) where A = 3- to 14-membered heterocyclyl, 5- to 20 14-membered heteroaryl, or C6-Ci0-aryl, depicted as compound 50 in Scheme 19, can be prepared from bromides 51. Bromides 51 can be coupled with commercially available stannanes 55 in a Stille cross-coupling, using e.g. LiCl, Pd(PPhs)4 in 1,4-dioxane at elevated temperatures, to give compounds of general formula 51. If not commercially available, stannanes 55 can be prepared using methods known to the person skilled in the art. WO 2025 / 012296 PCT / EP2024 / 069422 - 56 - Ri? R® Rv o-BU pBu 4b 558 Br 528 R? uU ‘2 5b ; Sh. 2a 2b 4a R R ‘ JL ov e) wR ren sille RV AL R Re ow ™ N a +cross-coupling o~ N now fe) Nay -4 R AY bea R Nay R° H LAs Re 51 55 50 R Scheme 19 5 Inone aspect, the present invention provides a process of manufacturing a compound of formula (Ia) described herein, or a pharmaceutically acceptable salt thereof comprising: reacting a first amine 1, wherein R**, R*>, R™*, R°>, R°, R®, and R’ are as defined herein, 4b pra RA R R Ro \e) H2N 6b ° 7 \6a R RR 1 with a second amine 3, wherein R!, R7*, R*®, R?, X, Y, and Z are as defined herein, | a Re Ry X LH x a Nv UZ OR “Y 10 3 in the presence of a base and a urea forming reagent, to form said compound of formula (Ia). In one embodiment, said base is selected from TEA, DIPEA and sodium bicarbonate. In a preferred embodiment, said base is selected from TEA and DIPEA. 15 Ina particularly preferred embodiment, said base is selected DIPEA. In one embodiment, said urea forming reagent is selected from bis(trichloromethyl) carbonate, phosgene, trichloromethyl chloroformate, (4-nitrophenyl)carbonate,1,1’-carbonyl-di-imidazole, and 1,1’-Carbonyl-di-(1,2,4-triazole). In a preferred embodiment, said urea forming reagent is 1,1’-Carbonyl-di-(1,2,4-triazole). WO 2025 / 012296 PCT / EP2024 / 069422 -57- In one aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, when manufactured according to any one of the processes described herein. SARM1 Inhibitory Activity 5 Compounds of the present invention are SARM1 inhibitors. Thus, in one aspect, the present invention provides the use of compounds of formula (I) as described herein for inhibiting the function of human SARM1 ina subject in need thereof. In a further aspect, the present invention provides compounds of formula (I) as described herein for use in a method of inhibiting the function of human SARM1 in a subject in need thereof. 10 Ina further aspect, the present invention provides the use of compounds of formula (1) as described herein for the preparation of amedicament for inhibiting the function of human SARM1 ina subject in need thereof. In a further aspect, the present invention provides a method for inhibiting the function of human SARM1 in a subject in need thereof, which method comprises administering an effective amount 15 of acompound of formula (I) as described herein to the subject. SARM1 inhibitory potency of the compounds of formula (I) according to the invention was measured using the following assay. Enzymatic reactions were ran ina 10uL volume consisting of 8nM human SARM1 (aa28-724), 100uM Nicotinamide (NMN) and 30uM Nicotinamide Adenine Dinculeotide (NAD). Assay 20 reagents were prepared in 25mM HEPES pH 7.2, 50mM NaCl, 1mM EDTA and 0.0025% Tween20. To determine compound ICso’s, reactions were incubated for 60minutes at room temperature in the presence of a 12-point concentration response curve of compound (starting concentration 100uM; 1 in 3 dilution between each point; 2% DMSO) and then quenched with 40uL of 0.125%Formic Acid. The peak area of NAD and linear ADPR were measured by a 25 RapidFire High Throughput Mass Spectrometry System (Agilent Technologies, Santa Clara, CA) using an API5000 triple quadrupole mass spectrometer (AB Sciex Framingham, MA). The ratio of linear ADPR to NAD peak area was then plotted against compound concentration to obtain an ICSO as fitted via non-linear regression. SARM1 inhibitory potencies of the compounds of formula (I) according to the invention as 30 measured in the assay described above are presented in Table 1. WO 2025 / 012296 PCT / EP2024 / 069422 - 58 - Table 1 Example | [Cso hSARMI1 Example | [Cso hSARMI1 [uM] [uM] p= pe a WO 2025 / 012296 PCT / EP2024 / 069422 -59- Example | [Cso hSARMI1 Example | [Cso hSARMI1 [uM] [uM] a == oe cn ep WO 2025 / 012296 PCT / EP2024 / 069422 - 60 - Using the Compounds of the Invention In one aspect, the present invention provides a compound of formula (1), or a pharmaceutically acceptable salt thereof, as described herein for use as atherapeutically active substance. 5 Ina further aspect, the present invention provides a method of treating or preventing a condition associated with SARM1 in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein. In a further aspect, the present invention provides a compound of formula (I) described herein, or 10 apharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein, for use in a method of treating or preventing a condition associated with SARM1 in a subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition 15 described herein, in a method of treating or preventing a condition associated withSARM1 ina subject in need thereof. In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method of treating or preventing a condition associated with SARM1 in a subject in need 20 thereof. In one embodiment, said condition associated with SARM1 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system. In one embodiment, said condition affecting the nervous system is neurodegenerative disorder. In one embodiment, said condition associated with SARM1 is selected from amyotrophic lateral 25 sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease. WO 2025 / 012296 PCT / EP2024 / 069422 -61- In a preferredembodiment, said condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, and multiple sclerosis. In a particularly preferred embodiment, said condition associated with SARM1 is amyotrophic 5 lateral sclerosis. In a particularly preferred embodiment, said condition associated with SARM1 is spinal muscular atrophy. In a particularly preferred embodiment, said condition associated with SARM1 is chemotherapy induced peripheral neuropathy. 10 Ina particularly preferred embodiment, said condition associated with SARM1 is diabetes induced peripheral neuropathy. In a particularly preferred embodiment, said condition associated with SARM1 is multiple sclerosis. Pharmaceutical Compositions and Administration 15 Inone aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (1) as described herein and a therapeuticallyinert carrier. In one embodiment, there is provided a pharmaceutical composition according to Example 83 or 84. The compounds of formula (I) and their pharmaceutically acceptable salts can be used as 20 medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions), nasally (e.g. in the form of nasal sprays) or rectally (e.g. in the form of suppositories). However, the administration can also be effected parentally, such as intramuscularly or intravenously (e.g. in the form of injection 25 solutions). The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the production of tablets, coated tablets, dragées and hard gelatin capsules. Lactose, corn starch or derivatives thereof, talc, stearicWO 2025 / 012296 PCT / EP2024 / 069422 - 62 - acid or its salts etc. can be used, for example, as such adjuvants for tablets, dragées and hard gelatin capsules. Suitable adjuvants for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi- solid substances and liquid polyols, etc. 5 Suitable adjuvants for the production of solutions and syrups are, for example, water, polyols, saccharose, invert sugar, glucose, etc. Suitable adjuvants for injection solutions are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc. Suitable adjuvants for suppositories are, for example, natural or hardened oils, waxes, fats, semi- 10 solid or liquid polyols, etc. Moreover, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity- increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still othertherapeutically valuable substances. 15 The dosage can vary in wide limits and will, of course, be fitted to the individual requirements in each particular case. In general, in the case of oral administration a daily dosage of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g. about 300 mg per person), divided into preferably 1-3 individual doses, which can consist, for example, of the same amounts, should be appropriate. It will, however, be clear that the upper 20 limit given herein can be exceeded when this is shown to be indicated. Examples The invention will be more fully understood by reference to the following examples. The claims should not, however, be construed as limited to the scope of the examples. In case the preparative examples are obtained as a mixture of enantiomers, the pure enantiomers 25 can be separated by methods described herein or by methods known to the man skilled in the art, such as e.g., chiral chromatography(e.g., chiral SFC) or crystallization. The compounds of formula I can contain several asymmetric centers and can be present in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers or mixtures of diastereoisomers. According to the Cahn-Ingold- WO 2025 / 012296 PCT / EP2024 / 069422 - 63 - Prelog Convention the asymmetric carbon atom can be of the "R" or "S" configuration. For the compounds described in the patent the absolute stereochemistry was arbitrarily assigned. The relative configuration at the tetrahydrofuran ring can be either cis or trans and was assigned arbitrarily. 5 All reaction examples and intermediates were prepared under an argon atmosphere if not specified otherwise. The compounds disclosed and described herein have been named using the IUPAC naming function of Biovia Draw 22.1. Where more than one name is associated with a Formula (1) compound or intermediate, the chemical structure shall define thecompound. 10 Example 1 1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(3 RS)-tetrahydrofuran-3-yl]urea _ Oo wee, a | N N Nw | oH To a solution of tetrahydrofuran-3-ylamine; hydrochloride (CAS RN: 204512-94-7; 45.37 mg, 367.13 umol) in DMF (734.27 uL) was added DIPEA (192.36 uL, 1.1 mmol) followed by CDT 15 (66.28 mg, 403.85 pmol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl-[(1S)-1-(4-pyridyl)ethyl]Jamine (CAS RN: 42732-16-1; 50 mg, 367.13 umol). The mixture was stirred at 70 °C for 20 h, before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SOu and evaporated. Purification by FC (SiOz; DCM / MeOH) and chiral SFC (Column chiral OZ-H, 5 um, 250x20 mm, 25% EtOH) gave the title 20 compound as a mixture of diastereomers (39.8 mg, 43%, tr = 2.485 min) and as a colorless oil. MS (ESI): m / z = 250.2 [M+H]* Example 2 1-methyl-3-[(3RS, 4RS or 3RS,4SR)-4-methyltetrahydrofuran-3-yl]-1-[(LS)-1-(4- pyridyl)ethyl]urea - .@) ao )N N Nw | 4H 25 WO 2025 / 012296 PCT / EP2024 / 069422 -64- To a solution of (4-methyltetrahydrofuran-3-yl)amine (CAS RN: 1527863-66-63; 7.14 mg, 367.13 umol) in DMF (734.27 wL) was added DIPEA (192.36 pL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 umol). The mixture was stirred at room temperature for 30 min before being treated with methyl-[(1S)-1-(4-pyridyl)ethylljamine (CAS RN: 42732-16-1; 50 mg, 367.13 pmol). The 5 mixture was stirred at 70 °C for 30 min before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SOu4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm, 40 mL / min, MeOH / H20+0.1% TEA) gave the title compound (20.3 mg, 20%, tr = 2.017 min) as a white oil. MS (ESI): m / z = 264.1 [M+H]* Example 3 10 1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(3 RS)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea e) : oO on Jus Nx | FF To a solution of [3-(trifluoromethyl)tetrahydrofuran-3-yl]amine;hydrochloride (CAS RN: 1638269-35-8,68 mg, 354.94 umol, ) in DCM (860 uL) was added DIPEA (220 uL, 1.29 mmol) followed by CDT (75 mg, 456.97 umol). The mixture was stirred at room temperature for 1 h. 15 Then, methyl-[(1S)-1-(4-pyridyl)ethylJamine (CAS RN: 42732-16-1; 48 mg, 50 wL, 352.45 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was extracted with DCM. The organic layers were washed with water and brine. The combined organic layers were dried over Na2SOq and evaporated. Purification by FC (Si02; DCM / MeOH) gave the title compound as a mixture of diastereomers (67 mg, 57%) and as an off-white solid. MS 20 (ESI): m / z =318.1 [M+H]* Example 4 3-[(3RS)-3-(1H-imidazol-2-yl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea e) : oO o~ Ouse (TON eve N 2 WO 2025 / 012296 PCT / EP2024 / 069422 - 65 - To a solution of [3-(1H-imidazol-2-yl)tetrahydrofuran-3-yl]amine;dihydrochloride (CAS RN 203 1269-25-5, 99.61 mg, 440.56 umol) in DMF (881.12 uL) was added DIPEA(230.83 uL, 1.32 mmol) followed by CDT (79.54 mg, 484.62 umol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl-[(1S)-1-(4-pyridyl)ethylJamine (CAS RN: 42732-16-1; 60 mg, 440.56 5 wumol). The resulting mixture was heated up at 75°C for 20 h before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SOq4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5um, 100x30mm, CH3CN / H20) gave the title compound as a mixture of diastereomers (9.2 mg, 6%) and as a colorless oil. MS (ESI): m / z = 316.1 [M+H]* 10 Example 5 1-methyl-3-[(3 RS)-3-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]-1-[(1S)-1-(4- pyridyl)ethyl]urea \e) = .@) A AWN N To a solution of [rac-(2S,3R)-2-(1-methylpyrazol-4-yl)tetrahydrofuran-3- 15 yljamine;dihydrochloride (CAS RN 1807941-18-9; 88.16 mg, 367.13 umol) in DMF (734.27 uL) was added DIPEA (192.36 uL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 pmol). The mixture was stirred at 75 °C for 30 min,before being treated with methyl-[(1S)-1-(4-pyridyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 mol). The mixture was heated up at 70 °C for 30 min before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried 20 over NazSOq and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 um, 100x30 mm, CH3CN / H20+0.1% HCOOH) gave the title compound as a mixture of diastereomers (70.9 mg, 53%) and as a white viscous oil. MS (ESI): m / z = 330.2 [M+H]* Example 6 3-[(2RS,3SR)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 25 —pyridyl)ethyljurea WO 2025 / 012296 PCT / EP2024 / 069422 - 66 - a N N OE K \ UN Br To a solution of [rac-(2S,3R)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]amine;dihydrochloride (CAS RN: 1955553-29-3; 116.02 mg, 367.13 pmol) in DMF (734.27 uL) was added DIPEA (142.35 mg, 192.36 uL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 pmol). The mixture was 5 stirred at 75 °C for 30 min, before being treated withmethyl-[(1S)-1-(4-pyridyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 umol). The mixture was heated up at 70 °C for 30 min before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over NazSOx4 and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 pm, 100 x 30 mm, 40 mL / min, CH3CN / H20+0.1% HCOOH) gave the title compound as a mixture of diastereomers 10 (80.2 mg, 53%) and as an off-white viscous oil. MS (ESI): m / z = 405.1 [M+H]" Example 7 1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(2RS,3SR)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran- 3-yljurea : L O Oo N7~ *~N (OE K \ ON N* 15 To a solution of [rac-(2S,3R)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3- ylJamine;trihydrochloride (CAS RN: 2241139-77-3; 128.74 mg, 367.13 umol) in DMF (734.27 uL) was added DIPEA (192.36 pL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 umol). The mixture was stirred at 75 °C for 30 min, before being treated with methyl-[(1S)-1-(4- pyridyl)ethyl]Jamine (CAS RN:42732-16-1; 50 mg, 367.13 umol). The mixture was heated up at 20 70 °C for 30 min before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SOq and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 um, 100 x 30 mm, 40 mL / min, CH3CN / H20+0.1% HCOOH) gave the title compound as a mixture of diastereomers (107 mg, 71%) and as a white solid. MS: (ESI): m / z = 404.2 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 -67- Example 8 3-[(2RS,3SR)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(LS)-1-(4- pyridyl)ethyl]urea _ oO Oo ) N N Nw pO \ UN 5 To a solution of [rac-(2S,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3- ylJamine; dihydrochloride (CAS RN: 2241140-72-5; 59 mg, 212.85 mol) in DMF (350 pL) was added DIPEA (0.140 uL, 817.84 pmol) followed by CDT (39 mg, 237.62 umol). The mixture was stirred at 50 °C for 1 hour, before being treated with methyl-[(1S)-1-(4-pyridyl)ethyl]amine (CAS RN: 42732-16-1; 28.8 mg, 30 uL, 211.47 umol). Themixture was heated up at 70 °C for 30 min 10 before being poured into EtOAc and 5% aq. LiCl-H20 solution. The aqueous layer was back- extracted with EtOAc. The organic layers were washed three times with 5% aq. LiCl-solution, once with water and once with brine. The organic layers were dried over Na2SOq and evaporated. Purification by FC (Si02; DCM / MeOH) gave the title compound as a mixture of diastereomers (43 mg, 53%) and as an off-white solid. MS (ESI): m / z = 367.2 [M+H]* 15 Example 9 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl ethyl]urea or 3-[(3S)- 4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(LS)-1-(4-pyridyl)ethyl]urea F F : O : O a | yoAn or a | yon Nx | oH Nx | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 20 58.58 mg, 367.13 umol) in DMF (734.27 uL) was added DIPEA (192.36 uL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 mol). The mixture was stirred at 75 °C for 30 min before being treated withmethyl-[(1S)-1-(4-pyridyl)ethylljamine (CAS RN: 42732-16-1; 50 mg, 367.13 pmol). The mixture was heated up at 75 °C for 1 h before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SO,4 and evaporated. Purification by HPLC WO 2025 / 012296 PCT / EP2024 / 069422 - 68 - (Gemini NX, 12 nm, 5 um, 100x30 mm, MeOH / H20+0.1% TEA) gave the title compound (20.6 mg, 19%, tr = 1.993 min) as colorless oil. MS(ESI): m / z = 286.1 [M+H]* Example 10 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(18)-1-(4-pyridyl)ethyl]urea or 3-[(3 R)- 5 4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]urea F F : O : O a yAne or a yn Nx | oH Nw | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 58.58 mg, 367.13 umol) and DIPEA (192.36 uL, 1.1 mmol) in DMF (734.27 uL) were added CDT (66.28 mg, 403.85 mol). The mixture was stirred at 75 °C for 30 min before being treated with 10methyl-[(1S)-1-(4-pyridyl)ethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 umol). The mixture was heated up at 75 °C for 1 h before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SOx and evaporated. Purification by HPLC (Gemini NX, 12 nm, 5 um, 100x30 mm, MeOH / H20+0.1% TEA) gave the title compound (23.2 mg, 21%, tr = 2.048 min) as colorless oil. MS(ESI): m / z = 286.1 [M+H]* 15 Example 11 3-[(2S,3 R)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyljurea or 3-[(2R,3S)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(LS)- 1-(4-pyridyl)ethyl]urea =~ ~~ Br Br 20 + Starting from 92 mg of Example 6: 3- / (2RS, 3SR)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1- methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea , chiral SFC (Column chiral IA, 5 um, 250x20 mm, 25% MeOH) gave the title compound (3.8 mg, 2%, tp = 2.549 min) and as a yellow viscous oil. MS (ESI): m / z = 405.1 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 - 69 - Example12 1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(2R,3S)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3- yljurea or 1-methyl-1-[(LS)-1-(4-pyridyl) ethyl]-3-[(2S,3R)-2-[5-(3-pyridyl)-3- pyridyl}tetrahydrofuran-3-yl]urea > AyAye > AwAAN / no | AO ML or no | HR NL~?% ore 5 ——~ —~ Starting from 52.6 mg of Example 7: / -methyl-1-[(1S)-1-(4-pyridyl) ethyl ]-3-[(2RS, 3SR)-2-[5-(3- pyridyl)-3-pyridyl ]tetrahydrofuran-3-yl]urea, chiral SFC (Column chiral Lux C4, 5 um, 250x20 mm, 40%MeQOH) gave the title compound (21.8 mg, 39%, tr = 3.746 min) and as a yellow viscous oil. MS (ESI): m / z = 404.2 [M+H]* 10 Example 13 3-[(2R,3S)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl) ethylJurea or 3-[(2S,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1- [(1S)-1-(4-pyridyl)ethylJurea or 5 15 Starting from 30 mg of Example 8: 3- / (2RS, 3SR)-2-(5-cyclopropyl-3-pyridyl) tetrahydrofuran-3- yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea, chiral SFC (Column chiral Lux C4, 5 um,250x20 mm, 30% MeOH) gave the title compound (13.4 mg, 42%, tr = 2.601 min) and as a colorless oil. MS (ESI): m / z = 367.3 [M+H]* Example 14 20 I-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)urea WO 2025 / 012296 PCT / EP2024 / 069422 - 70 - O F Oo N7~ ~N To a solution of (2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)amine (CAS RN: 1342056-79-4; 37.26 mg, 220.28 umol) in DMF (300 uL) was added DIPEA (76.94 pL, 440.56 umol) followed by CDT (52.22 mg, 286.36 pmol). The mixture was stirred at 50 °C for 1 h, before being treated 5 with methyl-[(1S)-1-(4-pyridylethyllamine (CAS RN: 42732-16-1; 30 mg, 31.25 uL, 220.28 umol). The mixture was heated up at 70 °C for 16 h before being poured into 2-Me-THF and washed with water and brine. The organic layers were dried over NazSO« and evaporated. Purification by RP-HPLC gave the title compound as a diasteromeric mixture (39 mg, 51% yield) and as a colorless amorphous solid. MS (ESI): m / z = 332.2 [M+H]* 10 Example 151-[(3-chloro-4-pyridyl) methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea F Cl oO F KAS? a | N N Nx | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 20 mg, 125.34 umol) in DMF (200 uL) was added DIPEA (109.46 uL, 626.72 umol) followed by 15 CDT (29.71 mg, 162.95 mol). The mixture was stirred at 50 °C for 1 h, before being treated with (3-chloro-4-pyridyl)methyl-methyl-amine;dihydrochloride (CAS RN: 2270911-80-1; 31.65 mg, 137.88 umol). The mixture was heated up at 70 °C for 16 h. Purification by RP-HPLC gave the title compound as a racemic mixture (24 mg, 60% yield) and as an off-white solid. MS (ESD): m / z = 306.1 [M+H]* 20 Example 16 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-[(3-fluoro-4-pyridyl) methyl]-1-methyl-urea WO 2025 / 012296 PCT / EP2024 / 069422 -7|- F F of KAS? ao | N N Nx | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 20 mg, 125.34 umol) in DMF (200 uL) was added DIPEA(109.46 uL, 626.72 umol) followed by CDT (29.71 mg, 162.95 umol). The mixture was stirred at 50 °C for 1 h, before being treated with 5 (3-fluoro-4-pyridyl)methyl-methyl-amine;dihydrochloride (CAS RN: 2460754-71-4; 26.71 mg, 125.34 umol). The mixture was heated up to 80 °C for 16 h, before being cooled down. Purification by RP-HPLC gave the title compound as a racemic mixture (24 mg, 63% yield) and as a white solid. MS (ESI): m / z = 290.2 [M+H]* Example 17 10 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-(4-pyridylmethyl)urea F O F KAS? ao | N N Nx | oH To a solution of 4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 17 mg, 106.54 umol) in DMF (170 pL) was added DIPEA (55.82 uL, 319.63 mol) followed by CDT (25.26 mg, 138.51 umol). The mixture was stirred at 50 °C for 1 h, before being treated with 15 methyl(4-pyridylmethyl)amine (CAS RN: 6971-44-4; 13.02 mg, 106.54 pmol). The mixture was heated up at 80 °C for 16h. Purification by RP-HPLC gave the titlecompound as a racemic mixture (10 mg, 33% yield) and as a colorless amorphous solid. MS (ESI): m / z = 272.2 [M+H]* Example 18 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea or 3-[(3S)- 20 4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyljurea or 3-[(3R)-4,4- difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propylJurea or _—-3-[(3R)-4,4- WO 2025 / 012296 PCT / EP2024 / 069422 -72- difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea F F Nw | 4H Nw | oH F F a yan or a yan i {J 1 o4 To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 86 mg, 538.98 mol) in DCM (1.2 mL) was added DIPEA (0.320 mL, 1.87 mmol) followed by 5 CDT (113 mg, 688.5 umol). The reaction mixture was stirred at 23 °C for 1 h before being treated with a solution of methyl(4-pyridylmethyl)amine (CAS RN: 6971-44-4; 80 mg, 532.55 wmol) in DCM (0.200 mL). The mixture was stirred at 23 °C for 3 h beforebeing poured into DCM and washed with water and brine. The aqueous layer was backextracted twice with DCM. The organic layers were dried over Na2SOq and evaporated. Purification by FC (SiOz, heptane / EtOAc) gave 10 two diastereomers A (70 mg) and B (57 mg). Starting from 70 mg of diasteromers A, chiral SFC (Column chiral Wrr C4, 5 um, 250x20 mm, 15% MeOH) gave the title compound (30 mg, 18%, tr = 4.280 min) as an off white solid. MS (ESI): m / z = 300.3 [M+H]* Example 19 15 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl) methyl]urea F O F AAS ao | N N Nx | oH To a solution of 4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 90 mg, 564.05 umol) in DMF (800 pL) was added DIPEA (246.28 pL, 1.41 mmol) followed by CDT (133.72 mg, 733.27 mol). The mixture was stirred at 50 °C for 1 h, before being treated 20 with methyl-[(3-methyl-4-pyridyl)methyllamine (CAS RN: 915919-59-4; 76.82 mg, 564.05 umol). The mixture was heated up at 70 °C for 1 h.Purification by RP-HPLC gave the title WO 2025 / 012296 PCT / EP2024 / 069422 -73- compound as a racemic mixture (117 mg, 69% yield) and as a colorless amorphous solid. MS (ESI): m / z = 286.2 [M+H]* Example 20 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(18)-1-pyridazin-4-ylethylJurea or 3- 5 [(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethylJurea or — 3- [GS)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyljurea or — 3- [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea F F F F To a solution of 4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 10 75.94 mg, 475.96 umol) in DMF (952 wL) was added DIPEA (498.76 uL, 2.86 mmol) followed by CDT (85.93 mg, 523.56 umol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl(1-pyridazin-4-ylethyl)amine;dihydrochloride (CAS RN: 2913244-09-2; 100 mg, 475.96 umol). The mixture was heated up at 70 °C for 2 h beforebeing poured into 2-Me-THF and washed with water and brine. The organic layers were dried over Na2SO« and evaporated. 15 Purification by FC (S102, DCM / MeOH) gave the title compound as a diasteromeric mixture (92 mg, 68% yield) and as white solid. MS (ESI): m / z 287.1 [M+H]* Starting from 92 mg of diasteromeric mixture, chiral SFC (Column chiral Whelk(r,r), 5 pm, 250x20 mm, 25% EtOH) gave the title compound (12.8 mg, 9% yield, tg = 2,572 min) as a white solid. MS (ESI): m / z = 287.1 [M+H]* 20 Example 21 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(18)-1-pyridazin-4-ylethylJurea or 3- [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethylJurea or — 3- [GS)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyljurea or — 3- WO 2025 / 012296 PCT / EP2024 / 069422 -74- [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea F F Now Now F F Now Now To a solution of 4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CASRN: 2408969-70-8; 75.94 mg, 475.96 umol) in DMF (952 uwL) was added DIPEA (498.76 uL, 2.86 mmol) followed 5 by CDT (85.93 mg, 523.56 mol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl(1-pyridazin-4-ylethyl)amine;dihydrochloride (CAS RN: 2913244-09-2; 100 mg, 475.96 umol). The mixture was heated up at 70 °C for 2 h before being poured into 2-Me-THF and washed with water and brine. The organic layers were dried over Na2SO« and evaporated. Purification by FC (Si02, DCM / MeOH) gave the title compound as a diasteromeric mixture (92 10 mg, 68% yield) and as white solid. MS (ESI): m / z = 287.1 [M+H]* Starting from 92 mg of diasteromeric mixture, chiral SFC (Column chiral Whelk(r,r), 5 pm, 250x20 mm, 25% EtOH) gave the title compound (13 mg, 9%, tr = 3.038 min) as a colorless oil. MS (ESI): m / z = 287.1 [M+H]* Example 22 15 3-{(38)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethylJurea or 3-[GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethylJurea or — 3- [GS)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyljurea or — 3- WO 2025 / 012296 PCT / EP2024 / 069422 -75 - [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea F F Now Now F F Now Now To a solution of 4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 75.94 mg, 475.96 umol) in DMF (952 pL) was added DIPEA (498.76 pL, 2.86 mmol) followed 5 by CDT (85.93 mg, 523.56 mol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl(1-pyridazin-4-ylethyl)amine;dihydrochloride (CAS RN: 2913244-09-2; 100 mg, 475.96 umol). The mixture was heated up at 70 °C for 2 h before being poured into 2-Me-THF and washed with water and brine. The organic layers were dried over Na2SO« and evaporated. Purification by FC (Si02, DCM / MeOH) gave the title compound as a diasteromeric mixture (92 10 mg, 68% yield) and as a whitesolid. MS (ESI): m / z = 287.1 [M+H]" Starting from 92 mg of diasteromeric mixture, chiral SFC (Column chiral Whelk(r,r), 5 pm, 250x20 mm, 25% EtOH) gave the title compound (14 mg, 10% yield, tg = 3.373 min) as a light yellow oil. MS (ESI): m / z = 287.1 [M+H]* Example 23 15 3-{(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea or 3-[(3R)-4,4- difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea F F a wane or a wn Nw | oH Nw | oH To a solution of 4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 70 mg, 438.71 umol) in DMF (700 pL) was added DIPEA (229.86 pL, 1.32 mmol) followed by 20 CDT (104. mg, 570.32 umol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl(4-pyridylmethyl)amine (CAS RN: 6971-44-4; 53.6 mg, 438.71 umol). The mixture was WO 2025 / 012296 PCT / EP2024 / 069422 - 76 - heated up at 80 °C for 1 h. Purification by HPLC (Gemini NX, 12 nm, 5 um, 100x30 mm, ACN / H20+0.1% TEA) gave the title compound as aracemic mixture (72 mg, 57% yield) and as a white solid. MS (ESI): m / z = 272.2 [M+H]* Starting from 72 mg of the racemic mixture, chiral SFC (Column chiral Whelk(r,r), 5 um, 250x20 5 mm, 23% EtOH) gave the title compound (32 mg, 44% yield, tg = 2.265 min) as a light yellow. MS (ESI): m / z = 272.2 [M+H]* Example 24 3-(4-benzoyltetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethylJurea - Oo 7 a var Nw | ; 10 To a solution of (4-aminotetrahydrofuran-3-yl)-phenyl-methanone;hydrochloride (EN300- 1693205; 83.59 mg, 367.13 umol) in DMF (734.27 uL) was added DIPEA (192.36 uL, 1.1 mmol) followed by CDT (66.28 mg, 403.85 mol). The mixture was stirred at 75 °C for 30 min, before being treated with methyl-[(1S)-1-(4-pyridyl)ethyl]Jamine (CAS RN: 42732-16-1; 50 mg, 367.13 umol). The mixture was heated up at 75 °C for 3 h before being poured into 2-Me-THF and washed 15 with water and brine. The organic layer was dried over Na2SOq and evaporated. Purification by RP-HPLC gave the title compound asa diasteromeric mixture (33 mg, 24% yield) and as a colorless oil. MS (ESI): m / z = 354.3 [M+H]* Example 25 1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(3 R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea or 1- 20 methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3- (trifluoromethyl) tetrahydrofuran-3-yl]urea : IL v : JL a; 2~-™~N7 NY or 2~-~N7 NT F 4 —F oren x orNN i Starting from 30.49 mg of Example 3: J / -methyl-1-[(1S)-1-(4-pyridylethyl]-3-[(3RS)-3- (trifluoromethyl) tetrahydrofuran-3-ylJurea, chiral SFC (Column chiral IC, 5 um, 250x20 mm, 15% MeOH) gave the title compound (6.7 mg, 21% yield, tg = 3.717 min) and as a colorless oil. 25 MS (ESI): m / z = 318.1 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 -77- Example 26 1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(3 R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea or 1- methyl-1-[(1S)-1-(4-pyridyl) ethyl]-3-[(3S)-3- (trifluoromethyl) tetrahydrofuran-3-yl]urea a N7~N“\E EOF a N7 ~N® 27 Na POA Nw |W LA 5 Starting from 3049 mg of Example 3:J / -methyl-1-[(1S)-1-(4-pyridylethyl]-3-[(3RS)-3- (trifluoromethyl) tetrahydrofuran-3-ylJurea, chiral SFC (Column chiral IC, 5 um, 250x20 mm, 15% MeOH) gave the title compound (5.1 mg, 16% yield, tg = 4.155 min) and as a colorless oil. MS (ESI): m / z = 318.1 [M+H]* Example 27 10 3-{(38)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyljurea or 3- [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea F F Za yan or a yoAn eo oo Starting from 117 mg of Example 19: 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3- methyl-4-pyridyl)methyl]urea, chiral SFC (Column chiral Whelk(r,r), 5 um, 250x20 mm, 25% 15 MeOH) gave the title compound (54 mg, 46% yield, tg = 2.493 min) and as a colorless amorphous solid. MS (ESI): m / z = 286.1 [M+H]* Example 28 1-[(3-bromo-4-pyridyl) methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea F Br O F AAS ao | N7 ~N Nw | oH WO 2025 / 012296 PCT / EP2024 / 069422 - 78 - To a solution of4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 500 mg, 3.13 mmol) in DMF (6.93 mL) was added DIPEA (2.53 mL, 14.51 mmol) followed by CDT (436.48 mg, 2.66 mmol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl-[1-(3-bromo-4-pyridyl)ethyl-]amine (CAS RN: 463941-58-4; 453.63 mg, 2.26 mmol). The 5 mixture was heated up at 70 °C for 16 h before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over Na2SOu and evaporated. Purification by FC (Si02, heptane / EtOAc / EtOH) gave the title compound as a racemic mixture (358.7 mg, 31% yield) and as a light yellow gum. MS (ESI): m / z = 350.1 [M+H]* Example 29 10 3-{(38)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyljurea or 3- [GS)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethylJurea or — 3- [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethylJurea or — 3-[GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea F F non | 4H Non |! 4H NY LY F F non | 4H Non |! 4H NY LY 15 Toasolution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 93.87 mg, 588.29 umol) in DCM (5 mL) were added DIPEA (410.97 uL, 2.35 mmol) and CDT (115.86 mg, 705.94 umol). The mixture was stirred at 23 °C for 1 h, before being treated with methyl-[1-(4-pyrimidyl)ethyl]amine;hydrochloride (102.15 mg, 588.29 umol). The mixture was stirred at 23 °C over 15 h. The solvent was removed in vacuo. Purification by FC (SiOz, 20 DCM / MeOH) gave the title compound as a diasteromeric mixture. Starting from the diasteromeric mixture, chiral SFC (Column chiral Whelk(r,r), 5 um, 250x20 mm, 15% EtOH) gave the title compound (33 mg, 19% yield, tg = 3.983 min) as a colorless oil. MS (ESI): m / z = 287.3 [M+H]* Step a): N-methyl-1-pyrimidin-4-yl-ethanamine WO 2025 / 012296 PCT / EP2024 / 069422 -79 - To a solution of 1-pyrimidin-4-ylethanone(CAS RN: 39870-05-8; 500.0 mg, 4.09 mmol) in DCE (2 mL) were added DIPEA (2.18 mL, 12.28 mmol) and MeNH2:HCI (822.89 mg, 12.28 mmol). The mixture was stirred at 50 °C for 1 h before being treated with sodium cyanoborohydride (771.8 mg, 12.28 mmol). The reaction was stirred at 50 °C for 12 h before being filtered off. The filtrate 5 was washed with DCM and concentrated to give the title compound (1856.0 mg, 83% yield) as a dark green oil. MS (ESI): m / z = 138.1 [M+H]* Step b): tert-butyl N-methyl-N-(1-pyrimidin-4-ylethyl)carbamate To a solution of N-methyl-1-pyrimidin-4-yl-ethanamine (8150.0 mg, 11.88 mmol) in MeOH (40 mL) were added BoczO (3889.6 mg, 17.82 mmol) and DIPEA (4.14 mL, 23.76 mmol). The 10 mixture was stirred at 25 °C for 1 h. Purification by FC (SiOz, PE / EtOAc) gave the title compound (2324.0 mg, 82% yield) as a light yellow oil. MS (ESI): m / z = 182.1 [M-C4aHs+H]* Step c): N-methyl-1-pyrimidin-4-yl-ethanamine, hydrochloride A solution of tert-butylN-methyl-N-(1-pyrimidin-4-ylethyl)carbamate (2815.0 mg, 11.86 mmol) in dioxane / HCl (30.0 mL, 60.0 mmol) was stirred at 25 °C for 2 h. The precipitate was collected 15 by filtration, washed by PE and dried under high vacuum to give the title compound (1.77 g, 80% yield) as a light brown solid. MS (ESI): m / z = 138.2 [M+H]* Example 30 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3-fluoro-4-pyridyl) ethyl]-1-methyl-urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl) ethyl]-1-methyl- 20 urea or 3-{(38)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1 R)-1-(-fluoro-4-pyridyl)ethyl]-1- methyl-urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]- 1-methyl-urea F F a ) : wane or ZA ) van or Nw | oH Nw | oH F F F 0 “Do F of 12: a yon or a An Nw | oH Nw | oH WO 2025 / 012296 PCT / EP2024 / 069422 - 80 - Starting from 127 mg of diasteromeric mixture (step d, 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-[1- (3-fluoro-4-pyridyl ethy]-1-methyl-urea), chiral SFC (Column chiral Whelk(r,r), 5 um, 250x20 mm, 11% EtOH) gave the title compound (31 mg, 21% yield, tz = 2.071 min) as a colorless oil. MS (ESI): m / z = 304.3 [M+H]* 5 Step a): 1-(3-fluoro-4-pyridyl)-N-methyl-ethanamine To a solution of 1-(3-fluoro-4-pyridyl)ethanone (2.0 g, 14.38 mmol) and MeNH2: HCI (2.9 g, 43.13 mmol) in DCE (20 mL) was added DIPEA (7.64 mL, 43.13 mmol). The mixture was stirred at 50 °C for lh before being treated with sodium cyanoborohydride (2.7 g, 43.13 mmol). The mixture was stirred at 70 °C for 12h before being concentrated under reduced pressure to give the title 10 compound (2.0 g, 90% yield) as a yellow oil which was used in the next step without any further purification. MS (ESI): m / z = 155.2 [M+H]* Step b): tert-butyl N-[1-(3-fluoro-4-pyridyl)ethyl]-N-methyl-carbamate To a solution of 1-(3-fluoro-4-pyridyl)-N-methyl-ethanamine (2 g, 12.97 mmol) in MeOH (20 mL) and TEA (1.3 g, 12.97 mmol) was added Boc20 (5662.62 mg, 25.94 mmol).The mixture was 15 stirred at 25°C for 2 h before being concentrated under reduced pressure. Purification by FC (SiOz, PE / EtOAc) gave the title compound (1.2 g, 36% yield) as a yellow oil. MS (ESI): m / z = 255.1 [M+H]" Step c): 1-(3-fluoro-4-pyridyl)-N-methyl-ethanamine ; dihydrochloride To a solution of tert-butyl N-[1-(3-fluoro-4-pyridyl)ethyl]-N-methyl-carbamate (1.2 g, 4.72 mmol) 20 in 1,4-dioxane (2 mL) was added a solution of HCl in 1,4-dioxane (20.0 mL, 40.0 mmol) The mixture was stirred at 25 °C for 1 h before being filtered and the cake dried under reduced pressure to give the title compound (710.31 mg, 66% yield) as a yellow solid. MS (ESD): m / z = 155.2 [M+H]" Step d): 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[1-(3-fluoro-4-pyridyl ethyl]-1-methyl-urea 25 Toa solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 89 mg, 557.78 umol) in DCM (1.4 mL) was added DIPEA (380 uL, 2.22 mmol) followed by CDT (117 mg, 712.87 pmol). The mixture was stirredat 23 °C for 1 h. Then, 1-(3-fluoro-4-pyridyl)- methyl-ethanamine;dihydrochloride (105 mg, 462.33 mmol) was added and the reaction mixture was stirred at 23 °C for 16 h. The reaction mixture was extracted with DCM. The organic layers WO 2025 / 012296 PCT / EP2024 / 069422 -8]- were washed with water and brine. The aqueous layer was backextracted twice with DCM. The combined organic layers were dried over Na2SO,4 and evaporated. Purification by FC (SiOz; heptane / EtOAc) gave the title compound as a diasteromeric mixture (127 mg, 90% yield). Example 31 5 3-{(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3-fluoro-4-pyridyl) ethyl]-1-methyl-urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl) ethyl]-1-methyl- urea or _—-3-{ (3.8)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1 R)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]- 1-methyl-urea F F a ) : wane or ZA van or Nw | oH n J | 4 F F F 0 “DoF of 12: a yA or a yn Nw | oH Nw | oH 10 Starting from 127 mg of diasteromeric mixture of Example 30, Step d_ (3-(4,4- difluorotetrahydrofuran-3-yl)-1-[1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea), chiral SFC (Column chiral Whelk(r,r), 5 um, 250x20 mm, 11% EtOH) gave the title compound (29 mg, 19%, tr = 2.250 min) as a colorless oil. MS (ESI): m / z = 304.3 [M+H]* 15 Example 32 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-[[3-(hydroxymethyl)-4-pyridyl]methyl]-1-methyl-urea F HO OF AAS? a | N N Nw | 4H To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 90.0 mg, 0.56 mmol) and DIPEA (0.59 mL, 3.38 mmol) in DMF (1 mL) was added CDT (120.34 20 mg, 0.73 mmol). The mixture was stirred at 50 °C for 1 h, before being treated with [4- WO 2025 / 012296 PCT / EP2024 / 069422 - 82 - (methylaminomethyl)-3-pyridyl]methanol;dihydrochloride (126.97 mg, 0.56 mmol). The mixture was stirred for 2 h at 80 °C, and for 18 h at 23 °C. Purification by RP-HPLC gave the title compound(10.1 mg, 6% yield) as a colorless oil. MS (ESI): m / z = 302.2 [M+H]* Step a): tert-butyl N-[(3-bromo-4-pyridyl) methyl]-N-methyl-carbamate 5 A solution of Boc20 (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3- bromo-4-pyridyl)-N-methyl-methanamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL), at 25 °C. The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (9.0 g, 96% yield) as a light yellow oil. MS (ESI): m / z = 301.0 / 303.0 [M+H]* Step b): methyl 4-[[tert-butoxycar bonyl(methyl)amino]methyl [pyridine-3-carboxylate 10 A mixture of tert-butyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (4.0 g, 13.28 mmol), triethylamine (2.22 mL, 15.94 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(IDdichloride dichloromethane complex (325.12 mg, 0.4 mmol) and MeOH (800 mL) was stirred at 130 °C for 28 h under carbon monoxide atmosphere (15000 mmHg), before being cooled down and evaporated. The residue was dilutedwith EtOAc (100 mL) and washed with 15 water (2x 50 mL). The organic layer was dried over Na2SOug, filtered and evaporated, to give the title compound (2.4 g, 59% yield). MS (ESI): m / z = 281.0 [M+H]* Step c): tert-butyl N-[[3-(hydroxymethyl)-4-pyridyl]methyl]-N-methyl-carbamate A solution of methyl 4-[[tert-butoxycarbonyl(methyl)amino|methyl]pyridine-3-carboxylate (500.0 mg, 1.78 mmol) in THF (5 mL) was added dropwise to a suspension of LiAIH4 (54.15 mg, 20 1.43 mmol) in THF (5 mL), at 0 °C. The mixture was stirred for 2 h at 0 °C before being allowed to warm up to 23 °C. Water (0.06 mL), 15% aqueous sodium hydroxide solution (0.06 mL) and then water (0.2 mL) were added to the reaction mixture at 0 °C, which was stirred for 1 h at 23 °C. The precipiate was then filtered off. The filtrate was evaporated, to give the title compound (470.0 mg, 99% yield). MS (ESI): m / z = 253.2 [M+H]* 25. Step d): [4-(methylaminomethyl)-3-pyridyl ]methanol, dihydrochloride To a solution of tert-butylN-[[3-(hydroxymethyl)-4-pyridyl]methyl]-N-methyl-carbamate (250.0 mg, 0.79 mmol) in DCM (4.44 mL) was added 4 M HCI in 1,4-dioxane (2.38 mL, 9.51 mmol). The mixture was stirred for 18 h at 23 °C, before being evaporated to give the title compound (130.0 mg, 73% yield) as a light yellow oil. MS (ESI): m / z = 153.2 [M+H]" WO 2025 / 012296 PCT / EP2024 / 069422 - 83 - Example 33 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridyl)ethyl]urea or 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4- 5 pyridyl)ethyl]urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl- 4-pyridyl)ethyl]urea F F F Fi e) e) Fi e) a ye a ye a yn Nw | 4H Nw | 4H Nw | 4H or or or F oF KAS? a | N N Nw | 4H To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 10 46.91 mg, 293.97 nmol) in DMF (587.94 uL) was addedDIPEA (308.05 wL, 1.76 mmol) followed by CDT (53.07 mg, 323.37 umol). The mixture was stirred at 50 °C for 1 h, before being treated with methyl-[1-(3-methyl-4-pyridyl)ethyl]jamine (CAS RN: 1550152-27-6; 55.2 mg, 293.97 umol). The mixture was stirred for 15 h at 70 °C, before being poured into 2-Me-THF and washed with water and brine. The organic layer was dried over NazSOu, filtered and evaporated. 15 Purification by FC (Si02; DCM / MeOH) and chiral SFC (Column chiral IF, 5 um, 250 x 20 mm, 15% MeOH) gave the title compound (7.7 mg, 9% yield, tz = 1.27 min) as a colorless oil. MS (ESI): m / z = 300.3 [M+H]* Example 34 1-[(3-cyclopropyl-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea F ° os O Aowdn ne J | 4H 20 To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 68.75 mg, 0.43 mmol) and DIPEA (0.45 mL, 2.59 mmol) in DMF (0.625 mL) was added 1-(3- cyclopropyl-4-pyridyl)-N-methyl-methanamine;dihydrochloride (101.32 mg, 0.43 mmol), at23 °C. The mixture was stirred at 50°C for 1 h, before being treated with 1-(3-cyclopropyl-4-pyridyl)- WO 2025 / 012296 PCT / EP2024 / 069422 - 84- N-methyl-methanamine;dihydrochloride (101.32 mg, 0.43 mmol). The mixture was stirred for 2 h at 80 °C, before being cooled down. Purification by RP-HPLC gave the title compound (77.4 mg, 58% yield) as a yellow liquid. MS (ESI): m / z = 312.2 [M+H]* Step a): tert-butyl N-[(3-bromo-4-pyridyl) methyl]-N-methyl-carbamate 5 A solution of Boc20 (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3- bromo-4-pyridyl)-N-methyl-methanamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25 °C. The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (9.0 g, 96% yield) as a light yellow oil. MS (ESI): m / z = 301.0 / 303.0 [M+H]* Step b): tert-butyl N-[(3-cyclopropyl-4-pyridyl)methyl]-N-methyl-carbamate 10 A solution of tert-butyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (300.0 mg, 1.0mmol) , potassium cyclopropyltrifluoroborate (515.9 mg, 3.49 mmol), tripotassium phosphate (634.32 mg, 2.99 mmol), and RuPhos (46.48 mg, 0.1 mmol) in toluene (4.8 mL) and water (1.2 mL) was degassed. Palladium(II) acetate (11.18 mg, 0.05 mmol) was added, and the mixture was stirred for 18 h at 100 °C ina sealed tube, before being cooled down. The mixture was diluted with 15 EtOAc (50 mL), and washed with a saturated aqueous KH2PO, solution (50 mL). The organic layer was washed with brine (50 mL), dried over Na2SOu, filtered, and evaporated. Purification by RP-HPLC gave the title compound (174.1 mg, 67% yield) as a light yellow oil. MS (ES): m / z = 263.2 [M+H]* Step c): 1-(3-cyclopropyl-4-pyridyl)-N-methyl-methanamine; dihydrochloride 20 Toa solution of tert-butyl N-[(3-cyclopropyl-4-pyridyl)methyl]-N-methyl-carbamate (110.0 mg, 0.42 mmol) in DCM (2.44 mL) was added 4 M HCI in 1,4-dioxane (1.26 mL, 5.03 mmol). The mixture was stirred for 18 h at 23 °C, before being evaporated to give thetitle compound (98.0 mg, 99% yield) as a white solid. MS (ESI): m / z = 163.0 [M+H]* Example 35 25 = 1-[(3-bromo-4-pyridyl) methyl]-3-[(38)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea or 1- [(3-bromo-4-pyridyl) methyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea aa aa Br [e) Br [e) new | oH new | oH or WO 2025 / 012296 PCT / EP2024 / 069422 - 85 - Starting from 162 mg of Example 28: = J / - / (3-bromo-4-pyridyl)methyl]-3-(4, 4- difluorotetrahydrofuran-3-yl)-1-methyl-urea, chiral SFC (Column chiral IF, 5 um, 250x20 mm, 25% MeOH) gave the title compound (63 mg, 39% yield, tp = 1.553 min) as a colorless oil. MS (ESI): m / z = 350. [M+H]* 5 Example 36 1-][3-(azetidin-1-yl)-4-pyridyl]methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea one Ae ees To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 46.0 mg, 0.29 mmol) and DIPEA (0.3 mL, 1.73 mmol) in DMF (0.50 mL) was added CDT (61.51 10 mg, 0.37 mmol). The mixture was stirred at 50 °C for 1 h,before being treated with 1-[3-(azetidin- 1-yl)-4-pyridyl]-N-methyl-methanamine;2,2,2-trifluoroacetic acid (149.72 mg, 0.29 mmol). The mixture was stirred for 2 h at 80 °C, before being cooled down. Purification by RP-HPLC gave the title compound (15.6 mg, 17% yield) as a yellow oil. MS (ESI): m / z = 327.2 [M+H]* Step a): tert-butyl N-[(3-bromo-4-pyridyl) methyl]-N-methyl-carbamate 15 A solution of Boc20 (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3- bromo-4-pyridyl)-N-methyl-methanamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL), at 25 °C. The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (9.0 g, 96% yield) as a light yellow oil. MS (ESI): m / z = 301.0 / 303.0 [M+H]* Step b): tert-butyl N-[[3-(azetidin-1-yl)-4-pyridyl]methyl]-N-methyl-carbamate 20 A solution of tert-butyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (300.0 mg, 1.0 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (57.64 mg, 0.1mmol), tris(dibenzylideneacetone)dipalladium (0) (45.61 mg, 0.05 mmol), azetidine hydrochloride (279.55 mg, 2.99 mmol) and cestum carbonate (1947.26 mg, 5.98 mmol) in 1,4-dioxane (15 mL) was sparged with Ar, before being stirred for 18 h at 100 °C. The mixture was cooled down and 25 filtered off. The filtrated was evaporated. Purification by RP-HPLC gave the title compound (72.2 mg, 26% yield) as a light yellow oil. MS (ESI): m / z = 278.2 [M+H]" Step c): 1-[3-(azetidin-1-yl)-4-pyridyl]-N-methyl-methanamine; 2,2,2-trifluoroacetic acid WO 2025 / 012296 PCT / EP2024 / 069422 - 86 - To a solution of tert-butyl N-[[3-(azetidin- 1-yl)-4-pyridyl]methyl]-N-methyl-carbamate (85.0 mg, 0.31 mmol) in DCM (2 mL) was added trifluoroacetic acid (0.12 mL, 1.53 mmol). The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (150.0 mg, 90% yield) as a light yellow oil. MS (ESI): m / z = 178.0 [M+H]* 5 Example 37 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2-phenoxy-1-(4-pyridyl)ethyl]urea ae oe ee To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (34.96 mg, 219.07 umol) in dichloromethane (1100 uL) was added DIPEA (250 uL, 1.46 mmol) followed by CDT (46.61 10 mg, 283.97 umol). The mixture was stirred for 1 h at 23 °C, before being treated with methyl-[2- phenoxy-1-(4-pyridyl)ethyl]amine (50 mg, 219.02 umol). The mixture was stirred for 16 h at 23 °C, before being evaporated. Purification by RP-HPLC gave the title compound (14.7 mg, 18% yield) as a white powder. MS (ESI): m / z = 378.3 [M+H]* Step a): N-methyl-2-phenoxy-1-(4-pyridyl)ethanamine 15 Titanium isopropoxide (2.1 mL, 7.09 mmol) was added at 0 °C over 2-5 min to a solution of 2- phenoxy-1-(4-pyridyl)ethanone (CAS RN: 1574141-85-7; 1440.0 mg, 6.75 mmol) in 2-propanol (9.65 mL). Then, methylamine ethanol (2.52 mL, 20.26 mmol) was added, and the mixture was allowed to warm up to 23 °C and stirred for another 18 h atthis temperature, before being cooled down to 0 °C. Sodium borohydride (383.2 mg, 10.13 mmol) was added portionwise, and the 20 mixture was stirred at 0 °C for 1 h before being diluted with EtOAc (2 mL) and brine (2 mL). The mixture was stirred for 10 min at 23 °C, before being filtered through celite. The organic layer was washed with brine, dried over NazSOu, filtered, and evaporated. Purification by FC (SiOz; DCM / MeOH 9:1) gave the title compound (550 mg, 36% yield) as a yellow oil. MS (ESI): m / z = 229.2 [M+H]* 25 Example 38 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-[2-methoxy-1-(4-pyridyl)ethyl]-1-methyl-urea WO 2025 / 012296 PCT / EP2024 / 069422 -87- b F oO F ne J ot 4H To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 42.71 mg, 267.69 pmol) in dichloromethane (1 mL) was added DIPEA (305.48 uL, 1.78 mmol) followed by CDT (56.95 mg, 346.99 umol). The mixture was stirred for 1 h at 23 °C, before being 5 treated with 2-methoxy-1-(4-pyridyl)ethanol(75 mg, 267.63 umol). The mixture was stirred for another 16 h at 23 °C before being evaporated. Purification by RP-HPLC gave the title compound (15 mg, 17% yield) as a light yellow solid. MS (ESI): m / z = 316.2 [M+H]* Step a): 2-methoxy-1-(4-pyridyl)ethanone To a solution of 4-bromopyridine (CAS RN: 1120-87-2; 6.5 g, 41.14 mmol) in THF (70 mL) was 10 added dropwise i-PrMgCl -LiCl in THF (79.11 mL, 102.85 mmol), at -20 °C under N2 atmosphere. The mixture was stirred for 1 h at this temperature, before being treated with N,2-dimethoxy-N- methyl-acetamide (CAS RN: 132289-57-7; 13.7 g, 102.85 mmol) in THF (15 mL). The mixture was stirred for 1 h at 0 °C, before being quenched with 30 mL of saturated aqueous NH4Cl. and poured into water. The mixture was extracted with EtOAc, and the combined organic layers were 15 washed with brine, dried over Na2SOu, filtered, and evaporated. Purification by FC (SiOz; PE / EtOAc 1:1) gave the title compound (5.0 g, 80% yield) as a colorless oil. 'H NMR (400MHz, CDCh) 6 = 8.85 - 8.76 (m, 2H), 7.77 - 7.66 (m, 2H), 4.67 (s, 2H), 3.50 ppm (s, 3H). Step b): 2-methoxy-1-(4-pyridyl)ethanol To a solution of 2-methoxy-1-(4-pyridyl)ethanone (3.0 g, 19.85 mmol) in MeOH (30 mL) at 0 °C 20 was added NaBHsg (1.5 g, 39.69 mmol). The mixture was stirred for 2 h at 23 °C, before being evaporated. Purification by FC (Si02; PE / EtOAc) gave the title compound (1.5 g, 49% yield) as a yellow oil. MS (ESI): m / z = 154.4 [M+H]* Step c): [2-methoxy-1-(4-pyridylethyl] methanesulfonate A solution of 2-methoxy-1-(4-pyridyl)ethanol (1.5 g, 9.79 mmol) in DCM (15 mL) and TEA (6.79 25 mL, 48.96 mmol) at 0°C was added Ms20 (5.1 g, 29.38 mmol). The mixture was stirred for 12 h at 25°C, before being evaporated. Purification by FC (SiOz; PE / EtOAc) gave the title compound (1.0 g, 44% yield) as a yellow oil. MS (ESI): m / z = 232.1 [M+H]" Step d): 2-methoxy-N-methyl-1-(4-pyridylethanamine WO 2025 / 012296 PCT / EP2024 / 069422 - 88 - A solution of [2-methoxy-1-(4-pyridyl)ethyl]methanesulfonate (1.0 g, 4.32 mmol) in 2 M MeNH2 solution in THF (32.43 mL, 64.86 mmol). The mixture was stirred for 12 h at 70 °C, before being evaporated, giving the crude title compound (846.0 mg, 82% yield) as a yellow oil. MS (ESI): m / z = 167.2 [M+H]* 5 Example 39 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-[(3-methoxy-4-pyridyl) methyl]-1-methyl-urea aA axe) fe) new | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 30 mg, 188.02 pmol) and DIPEA (82 uL, 469.51 umol) in DCM (450 uL) was treated with CDT 10 (45 mg, 246.77 pmol). The mixture was stirred for 1 h at 23 °C, before being treated with (3- methoxy-4-pyridyl)methyl-methyl-amine (29 mg, 190.55 mol). The mixture was stirred for 16h at 23 °C, before being poured into EtOAc (10 mL). The mixture was washed three times with water and brine. The aqueous layers were back-extracted with EtOAc (20 mL). The combined organic layers were dried over NazSOa, filtered, and evaporated.Purification by FC (SiOz; 15 heptane / EtOAc / MeOH) gave the title compound (33.5 mg, 56% yield) as a white powder. MS (ESI): m / z = 302.2 [M+H]* Step a): (3-methoxy-4-pyridyl)methyl-methyl-amine To a solution of 3-methoxyisonicotinaldehyde (CAS RN: 1849-52-1; 100 mg, 729.18 umol) and methylamine hydrochloride (247 mg, 3.66 mmol) in MeOH (2 mL) was added sodium 20 triacetoxyborohydride (473 mg, 2.23 mmol). The mixture was stirred for 18 h at 23 °C, before being treated with 2 M HCI (2 mL) and evaporated. The residue was dissolved in 2 M NaOH. The aqueous phase was extracted with DCM, and the combined organic layers were dried over Na2SOa, filtered, and evaporated, to give the crude title compound (60 mg, 52% yield) as a light yellow liquid. MS (ESI): m / z = 153.2 [M+H]* 25 Example 40 1-[1-(3-chloro-4-pyridyl) ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea WO 2025 / 012296 PCT / EP2024 / 069422 - 89 - F Cl QF KAS? a N N n oJ 1 4 To a solution of(4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 38.53 mg, 241.49 umol) in DCM (599.38 uL) was added DIPEA (144.65 pL, 845 pmol) followed by CDT (59.44 mg, 362.14 umol). The mixture was stirred for 1 h at 23 °C, before being treated 5 with 1-(3-chloro-4-pyridyl)-N-methyl-ethanamine;dihydrochloride (50 mg, 241.43 umol) and stirred for another 16 h at 23 °C. The mixture was extracted with DCM and water. The aqueous layer was back-extracted twice with DCM. The organic layers were washed with brine. The combined organic layers were dried over sodium sulfate, filtered and evaporated. Purification by RP-HPLC gave the title compound (22.4 mg, 28% yield) as a white oil. MS (ESI): m / z = 320.1 10 [M+H]° Step a): tert-butyl N-[1-(3-chloro-4-pyridyl)ethyl]-N-methyl-carbamate A mixture of 1-(3-chloro-4-pyridyl)-N-methyl-ethanamine (CAS RN: 1602674-56-5; 2194.0 mg, 12.86 mmol), Boc20 (4.2 g, 19.29 mmol) in MeOH (60 mL) was stirred for 1 h at 25 °C, before beingevaporated. Purification by FC (SiOz; PE / EtOAc) gave the title compound (2.0 g, 57% yield) 15 asacolorless oil. MS (ESI): m / z = 271.0 [M+H]* Step b): 1-(3-chloro-4-pyridyl)-N-methyl-ethanamine ; dihydrochloride A solution of tert-butyl N-[1-(3-chloro-4-pyridyl)ethyl]-N-methyl-carbamate (1.0 g, 3.69 mmol) in 2 M HCI in 1,4-dioxane (30.0 mL, 60.0 mmol) was stirred for 4 h at 23 °C. The resulting precipitate was filtered, and the cake was dissolved in MeOH (40 mL), before being evaporated to 20 give the title compound (812.1 mg, 90% yield) as a light yellow solid. MS (ESD: m / z = 171.1 [M- 2 HC1+ H]* Example 41 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-pyrrolidin-1-yl-4-pyridyl) methyl]urea F WW QF KAS ao N* *N n oJ 1 oH WO 2025 / 012296 PCT / EP2024 / 069422 - 90 - To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 265.0 mg, 1.66 mmol) and DIPEA (1.74 mL, 9.96 mmol) in DMF (3.13 mL) was added CDT (354.35 mg, 2.16 mmol). The mixture was stirredat 50 °C for 1 h, before being treated with N- methyl-1-(3-pyrrolidin-1-yl-4-pyridyl)methanamine;trihydrochloride (499.32 mg, 1.66 mmol). 5 The mixture was heated to 80 °C and stirred for 2 h at this temperature, before being cooled down. Purification by RP-HPLC gave the title compound (53.8 mg, 9% yield) as a yellow oil. MS (ESI): m / z = 341.4 [M+H]" Step a): tert-butyl N-[(3-bromo-4-pyridyl) methyl]-N-methyl-carbamate A solution of Boc20 (7163.92 mg, 32.82 mmol) was added dropwise to a stirred solution of 1-(3- 10 bromo-4-pyridyl)-N-methyl-methanamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL), at 25 °C. The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (9.0 g, 96% yield) as a light yellow oil. MS (ESI): m / z = 301.0 / 303.0 [M+H]* Step b): tert-butyl N-methyl-N-[(3-pyrrolidin-1-yl-4-pyridyl)methyl]carbamate A solution of tert-butyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate (1.6 g, 5.31 mmol), 159,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (153.7 mg, 0.27 mmol), tris(dibenzylideneacetone)dipalladium (0) (243.23 mg, 0.27 mmol), pyrrolidine (1133.46 mg, 15.94 mmol) and cesium carbonate (5.19 g, 15.94 mmol) in 1,4-dioxane (80 mL) was stirred for 18 hat 100 °C. Purification by FC (SiOz; MTBE / MeOH) gave the title compound (500.0 mg, 32% yield) as a light yellow oil. MS (ESI): m / z = 292.2 [M+H]* 20. Step c): N-methyl-1-(3-pyrrolidin-1-yl-4-pyridyl)methanamine, trihydrochloride To a solution of tert-butyl N-methyl-N-[(3-pyrrolidin-1-yl-4-pyridyl)methyl]carbamate (500.0 mg, 1.72 mmol) in DCM (10 mL) was added a solution of 4 M HCI in 1,4-dioxane (5.15 mL, 20.59 mmol). The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (500.0 mg, 87% yield) as a light yellow solid. MS (ESI): m / z = 192.0 [M+H]* 25 Example 42 1-[(S)-cyclopropyl(4-pyridyl) methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea or 1-[(S)-cyclopropyl(4-pyridyl)methyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea or 1-[(R)-cyclopropyl(4-pyridyl) methyl]-3-[(38)-4, 4-difluorotetrahydrofuran-3-yl]-1- WO 2025 / 012296 PCT / EP2024 / 069422 -9] - methyl-urea or 1-[(R)-cyclopropyl(4-pyridyl) methyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3- yl]-1-methyl-urea V oF F V oF F oF F a7 J a7 J apody or or or F oh a N N n oJ 1 4 5 1-[Cyclopropyl(4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea (52.0 mg, 0.17 mmol) was separated by chiral SFC (Column CHIRALCEL OJ-H5, 5 um, 250x20 mm, hexane:IPA:MeOH 90:5:5) to give the title compound (6.3 mg, 12% yield, tg = 0.695 min) as a colorless oil. MS (ESI): m / z = 312.2 [M+H]* Step a): 1-cyclopropyl-N-methyl-1-(4-pyridyl) methanamine 10 A solution of cyclopropyl(4-pyridyl)methanone (CAS RN: 39512-48-6; 900.0 mg, 6.11 mmol) and monomethylamine in THF (20% wt, 1.81 mL, 9.17 mmol) in THF (10 mL) was cooled down to 0°C, before being treated dropwise with titantum(IV) isopropylate (2.61 g, 9.17mmol). The mixture was stirred for 16 h at 23 °C, before before being cooled down to 0 °C and treated with sodium borohydride (462.69 mg, 12.23 mmol). The mixture was stirred for 16 h before being 15 treated with MeOH (10 mL) and sodium borohydride (102.82 mg, 2.72 mmol) at 0°C. The reaction was stirred for another 2 h at 23 °C, before being treated with ice-cold water. The mixture was extracted with EtOAc, and the combined organic layers were dried over NazSOu, filtered, and evaporated, to give the title compound (800.0 mg, 57% yield) as a light yellow oil. MS (ESI): m / z = 163.0 [M+H]" 20 Step b): 1-{cyclopropyl(4-pyridyl)methyl]-3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-urea To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 50.0 mg, 0.31 mmol) and DIPEA (0.14 mL, 0.78 mmol) in DMF (0.500 mL) was added CDT (66.86 mg, 0.41 mmol), at 23 °C. The mixture was stirred for 1 h at 50 °C, before being treated with1-cyclopropyl-N-methyl-1-(4-pyridyl)methanamine (101.68 mg, 0.31 mmol). The mixture WO 2025 / 012296 PCT / EP2024 / 069422 -92- was stirred for 2 h at 80 °C and for 18 h at 23 °C. Purification by RP-HPLC gave the title compound (28.0 mg, 27% yield) as a light brown oil. MS (ESI): m / z = 312.2 [M+H]" Example 43 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea F oF KAS? a | N N Nw | 4H 5 To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (36.08 mg, 226.11 umol) (CAS RN: 2408969-70-8) in dichloromethane (452.22 wL) was added DIPEA (96.43 mg, 130.32 uL, 746.17 pmol) followed by CDT (55.66 mg, 339.17 umol). The mixture was stirred at 23°C for 1 h, before being treated with methyl-[1-(4-pyridyl)cyclopropyl]amine;dihydrochloride (CAS 10 RN: 2416728-56-6; 50 mg, 226.11 mol). The mixture was stirred for 48 h at 23 °C, before being extracted with 2-Me-THF. The organic layers were washed with water and brine. The combined organic layers were dried overNazSOu« and evaporated. Purification by RP-HPLC gave the title compound (29.3 mg, 41% yield) as a white oil. MS (ESI): m / z = 298.3 [M+H]* Example 44 15 3-[(2R,38)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethylJurea or 3-[(2S,3R)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1- methyl-1-[(1S)-1-(4-pyridyl) ethyl]urea A Ayn f Aan \_N \ UN Br Br or A suspension of (2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3- 20 amine;dihydrochloride (62.0 mg, 0.19 mmol) in DCM (2 mL) was cooled down to 0 °C, before being treated with triethylamine (0.1 mL, 0.75 mmol) and CDT (33.51 mg, 0.21 mmol). The mixture was stirred for 1 h at this temperature, and (1S)-N-methyl-1-(4-pyridylethanamine (CAS RN: 42732-16-1; 25.59 mg, 0.19 mmol) was added. The mixture was stirred at 20 °C for 15 h and concentrated. Purification by RP-HPLC gave 50.5 mg of racemic mixture. Purification by chiral WO 2025 / 012296 PCT / EP2024 / 069422 - 93 - SFC (Column: CHIRALPAK IC,250x21 mm, 5 um, hexane: IPA:MeOH 70:15:15, 18 mL / min) gave the title compound (16.1 mg, 20% yield, tg = 24.47 min) as a light brown solid. MS (ESI): m / z = 419.0 / 421.0 [M+H]* Step a): (2S, 3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-car boxylic acid 5 A solution of 5-bromo-2-methyl-pyridine-3-carbaldehyde (CAS RN: 1211532-24-9; 250.0 mg, 1.25 mmol) and methyl 4-chlorobutyrate (CAS RN: 3153-37-5; 187.75 mg, 1.37 mmol) in THF (3 mL) was cooled down to -30 °C, before being treated with sodium tert-butoxide (180.16 mg, 1.87 mmol). The mixture was stirred for 1 h at this temperature, before being warmed up to 25 °C and stirred for another 15 h. The mixture was evaporated and dissolved in MeOH (2 mL). A 10 solution of potassium hydroxide (105.18 mg, 1.87 mmol) in water (2 mL) was added. The resulting mixture was stirred for 2 h at 23 °C, before being evaporated. The residue was dissolved in water (2 mL), and the aqeous layer was extratcted with MTBE. The aqueous layer was separatedand acidified with saturated aqueous NaHSO, solution to pH=4. The mixture was extracted with EtOAc. The combined organic layers were dried over Na2SOa, filtered, and evaporated, to give the 15 crude title compound (260.0 mg, 55% yield) as a white solid. MS (ESI): m / z = 286.0 / 288.0 [M+H]* Step b): tert-butyl N-[QR, 3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]carbamate To a solution of (28,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-carboxylic acid (260.0 mg, 0.91 mmol) and triethylamine (0.19 mL, 1.36 mmol) in ¢ert-butanol (7.8 mL, 82.19 mmol) was added diphenylphosphonic azide (0.2 mL, 0.91 mmol) dropwise, at 23 °C. The mixture was 20 heated at 80 °C for 15 h and evaporated. The residue was dissolved in EtOAc, and the solution was washed with water. The organic layer was dried over sodium sulfate, filtered, and evaporated. Purification by FC (S102; hexane / EtOAc 3:1) gave the title compound (110.0 mg, 33% yield) as a white solid. MS (ESI): m / z = 356.7 / 358.7 [M+H]*Step c): (2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-amine; dihydrochloride 25 To a solution of tert-butyl N-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3- yl]carbamate (72.0 mg, 0.2 mmol) in DCM (2 mL) was added 4 M HCI in 1,4-dioxane (0.5 mL, 10.0 eq). The mixture was stirred at 20 °C for 15 h, before being evaporated to give the crude title compound (64.0 mg, 96% yield) as a white solid. MS (ESI): m / z = 257.0 / 259.0 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 -94- Example 45 1-[(1S)-1-(3-chloro-4-pyridyl) ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea or 1-[(1S)-1-(3-chloro-4-pyridyl) ethyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea or 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- 5 methyl-urea or 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea F F F cl. OQ ne: cl. Q 0 cl 9 ne: a yodys a yoAn a yodys Nx | 4H Nx | 4H Nx | 4H or or or F Cl oF AAS? a | N NNx | 4H Starting from 224 mg of Example 40: = / - / / -(3-chloro-4-pyridylethyl]-3-(4,4- 10 difluorotetrahydrofuran-3-yl)-1-methyl-urea, chiral SFC (chiral Whelk(r,r), 12 nm, 5 um, 250 x 20 mm, W(r,r) 80 mL 18% EtOH) gave the title compound (0.95 mg, 5% yield, tg = 2.11 min) as a white oil. MS (ESI): m / z = 320.1 [M+H]" Example 46 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea or 3- 15 [GS)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea F F ie ie 0) 0) Za ) yoAn 7 ) yodys Nx | 4H Nx | 4H or Starting from 40.0 mg of Example 43: 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4- pyridyl) cyclopropyl]urea, chiral SFC (chiral Whelk(,r), 5 um, 250 x 20 mm, 30% MeOH) gave the title compound (8.0 mg, 40% yield, tg = 2.15 min) as a white oil. MS (ESI): m / z = 298.1 20 [M+H]° WO 2025 / 012296 PCT / EP2024 / 069422 - 95 - Example 47 1-[[3-(3-chloroanilino)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea or1-[[3-(3-chloroanilino)-4-pyridyl]methyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea Cl Cl C. . a NH fe) ne: NH fe) pe: Za yan Za yan n J 1 oH n J 1 oH 5 or To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 48.44 mg, 303.57 nmol) in DCM (940 uL) was added DIPEA (212.07 uL, 1.21 mmol), followed by the addition of CDT (59.79 mg, 364.28 umol) at 23 °C. The mixture was stirred for 1 h at 23 °C, before being treated with a solution of [3-(3-chloroanilino)-4-pyridyl]methyl-methyl-amine 10 (75.2 mg, 303.57 umol) in DCM (940 uL). The mixture was stirred for another 1.5 h at 23 °C, before being treated with water and evaporated. Purification by FC (Si02; DCM / MeOH) followed by chiral SFC (Column chiral AD-H, 5 um, 250 x 20 mm, 18% MeOH) gave the title compound (24.4 mg, 22% yield) as a white solid. MS (ESI): m / z = 397.3 [M+H]" Step a): tert-butyl N-[(3-bromo-4-pyridyl) methyl]-N-methyl-carbamate 15 A solution of Boc20 (7163.92 mg, 32.82mmol) was added dropwise to a stirred solution of 1-(3- bromo-4-pyridyl)-N-methyl-methanamine (CAS RN: 463941-58-4; 6.0 g, 29.84 mmol) in DCM (30 mL), at 25 °C. The mixture was stirred for 18 h at 23 °C before being evaporated, to give the title compound (9.0 g, 96% yield) as a light yellow oil. MS (ESI): m / z = 301.0 / 303.0 [M+H]* Step b): N-[[3-(3-chloroanilino)-4-pyridyl]methyl]-N-methyl-carbamic acid tert-butyl ester 20 A solution of 3-chloroaniline (58.76 wL, 557.31 wmol), N-[(3-bromo-4-pyridyl)methyl]-N- methyl-carbamic acid tert-butyl ester (111.9 mg, 371.54 umol) and cesium carbonate (302.64 mg, 928.85 umol) in toluene (1.17 mL) was degassed under Nitrogen, before being treated with palladium diacetate (8.34 mg, 37.15 wmol) and racemic-2,2'-bis(diphenylphosphino)-1, 1'- binaphthyl (46.27 mg, 74.31 wmol). The mixture was stirred at 100 °C for 16 h, before being 25 poured into 2-methyl-THF and washed with water and brine. The organic layer was dried over WO 2025 / 012296PCT / EP2024 / 069422 - 96 - Na2SOu, filtered, and evaporated. Purification by FC (SiOz; heptane / EtOAc) gave the title compound (65.7 mg, 50.84% yield) as a light brown oil. MS(ESI): m / z = 348.3 [M+H]* Step c): [3-(3-chloroanilino)-4-pyridyl]methyl-methyl-amine A solution of N-[[3-(3-chloroanilino)-4-pyridyl]methyl]-N-methyl-carbamic acid tert-butyl ester 5 (175.6 mg, 504.83 umol) in 4 M HCI in 1,4-dioxane (2.52 mL, 10.1 mmol) was stirred for 18 h at 23 °C, before being diluted with DCM, filtered over celite, and evaporated. Purification by FC (Si02; DCM / MeOR) gave the title compound (83.9 mg, 60.38% yield) as a light brown oil. MS (ESI): m / z = 248.1 [M+H]* Example 48 10 3-{(3S)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea or 3-[(3R)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyljurea F F - of - of : 0) : 0) Za ) yan Za ) An NS NS or To a solution of 4,4-difluoro-3-methyl-tetrahydrofuran-3-carboxylic acid (CAS RN:1782346-79- 15 5; 100.0 mg, 0.6 mmol) and triethylamine (0.13 mL, 0.9 mmol) in 1,4-dioxane (1.25 mL) was added diphenylphosphoryl azide (182.23 mg, 0.66 mmol), at 23 °C. The mixture was stirred for 1 h at 60 °C and for 2 h at 80 °C, before being cooled down and treated with (1S)-N-methyl-1-(4- pyridyl)ethanamine (CAS RN: 42732-16-1; 81.99 mg). The mixture was stirred for 1 h at 23 °C, before being purified by RP-HPLC. Chiral SFC (Column Chiralpak IG, 250x20 mm, 5 pm, 20 hexane / IPA / MeOH 70:15:15, 14 mL / min) gave the title compound (36.5 mg, 20.26% yield, tr = 16.17 min) as a yellow oil. MS (ESI): m / z = 300.0 [M+H]* Example 49 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1 R)-2-phenoxy-1-(4-pyridyl)ethyljurea or 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4- 25 pyridyl)ethylJurea or 3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1- (4-pyridyl)ethyl]urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea WO 2025 / 012296 PCT / EP2024 / 069422 -97- A J ahh A Se: or or or a N N n J | 4H To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 5 174.78 mg, 1.1 mmol) in DCM (5.5 mL) was added DIPEA (1.25 mL, 7.3 mmol) followed by CDT (233.03 mg, 1.42 mmol). The mixture was stirred at 23 °C for 1 h, before being treated with N-methyl-2-phenoxy-1-(4-pyridyl)ethanamine (250 mg, 1.1 mmol) and stirred for 16 h at 23 °C. Purification by FC (S102; DCM / MeOH) gave 340 mg of the racemic mixture. Purification by chiral SFC (Column chiral Whelk(r,r), 5 um, 250 x 20 mm, 25% MeOH) gave the title compound (46 10 mg, 11% yield, tk = 3.06 min) as a white powder. MS (ESI): m / z = 378.2 [M+H]* Step a): N-methyl-2-phenoxy-1-(4-pyridyl)ethanamine Titanium isopropoxide (2.1 mL, 7.09 mmol) was added at 0 °C over 2-5 min to a solution of 2- phenoxy-1-(4-pyridyl)ethanone (CAS RN: 1574141-85-7; 1440.0 mg, 6.75 mmol) in 2-propanol (9.65 mL). Then,methylamine ethanol (2.52 mL, 20.26 mmol) was added, and the mixture was 15 allowed to warm up to 23 °C and stirred for another 18 h at this temperature, before being cooled down to 0 °C. Sodium borohydride (383.2 mg, 10.13 mmol) was added portionwise, and the mixture was stirred at 0 °C for 1 h before being diluted with EtOAc (2 mL) and brine (2 mL). The mixture was stirred for 10 min at 23 °C, before being filtered through celite. The organic layer was washed with brine, dried over NazSOu, filtered, and evaporated. Purification by FC (SiOz; 20 DCM / MeOH) gave the title compound (550 mg, 36% yield) as a yellow oil. MS (ESD): m / z = 229.2 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 - 98 - Example 50 1-methyl-3-[(LR,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridyl)ethyljurea or —1- methyl-3-[(1S, 5S)-3-oxabicyclo[3.1. 0J / hexan-1-yl]-1-[(1S)-1-(4-pyridyl)ethylJurea : [e) : [e) ay oN ASR or ZN yay ad 5 Toa solution of [3-oxabicyclo[3.1.0]hexan-1-yl]Jamine;hydrochloride (CAS RN:2307776-44-7; 49.78 mg, 367.13 pmol) in DCM (734.27 pL) was added DIPEA (147.47 wL, 844.41 pmol) followed by CDT (90.38 mg, 550.7 umol).The mixture was stirred at at 23 °C for 1 h before being treated with methyl-[(1S)-1-(4-pyridylethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 pmol). The mixture was stirred at 23°C for 16 h before being poured into 2-Me-THF and washed with 10 water and brine. The combined organic layers were dried over Na2SOz and evaporated. Purification by (Gemini NX, 12 nm, 5 um, 100 x 30 mm, ACN / H20 + 0.1% TEA) gave the title compound as a mixture of diasteromers (55.3 mg, 55% yield) and as a white oil . MS (ESI): m / z = 262.3 [M+H]+ Starting from 40 mg of diasteromeric mixture, chiral SFC (Column chiral AD-H, 5 um, 250 x 20 mm, 15 % MeOH) gave the title compound (9.3 mg, 23% yield, tg = 3.420 min) as a light yellow 15 oil. MS (ESD: m / z = 262.2 [M+H]* Example 51 1-methyl-3-[(LR,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridyl)ethyljurea or —1- methyl-3-[(1S,5S)-3-oxabicyclo[3.1. 0J / hexan-1-yl]-1-[(1S)-1-(4-pyridyl)ethylJurea : [e) : [e) ay oN ASR or ZN yay ad 20 To a solution of [3-oxabicyclo[3.1.0]hexan-1-yl]amine;hydrochloride (CAS RN: 2307776-44-7; 49.78 mg, 367.13 pmol) in DCM (734.27 pL) was added DIPEA (147.47 wL, 844.41 pmol) followed by CDT (90.38 mg, 550.7 umol).The mixture was stirred at at 23 °C for 1 h before being treated with methyl-[(1S)-1-(4-pyridylethyl]amine (CAS RN: 42732-16-1; 50 mg, 367.13 pmol). The mixture was stirred at 23 °C for 16 h before being poured into 2-Me-THF and washed with 25 water and brine. The combined organic layers were dried over Na2SOuz and evaporated. Purification by (Gemini NX, 12 nm, 5 um, 100 x 30 mm, ACN / H20 + 0.1% TEA) gave the title compound as a mixture of diasteromers (55.3 mg, 55% yield) and as a white oil. MS (ESI): m / z = 262.3 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 - 99 - Starting from 40 mg of diasteromeric mixture, chiral SFC (Column chiral AD-H, 5 um, 250 x 20 mm, 15% MeOH) gavethe title compound (10.1 mg, 25% yield, tg = 3.610 min) as a light yellow oil. MS (ESI): m / z = 262.2 [M+H]* Example 52 5 1-{[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea or 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea F F F_UF O ce: F_UF oF Ds a yon or a wAn Nx | oH Nx | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 10 40 mg, 250.69 nmol) in DCM (600 pL) were added DIPEA (110 pL, 629.84 pmol) and CDT (60 mg, 329.03 wmol). The mixture wasgg stirred at 23 °C for 1 h. [3-(difluoromethyl)-4- pyridyl]methyl-methyl-amine (44 mg, 255.55 pmol) was added. The reaction mixture was stirred at 23 °C for 16 h. The combined organic layers were dried over NazSO,4 and evaporated. Purification by (S102, DCM / MeOH) and SFC (chiral Whelk(r,r), 12 nm, 5 um, 250 x 20 mm, 20% 15 MeOH) gave the title compound (32.3 mg, 38% yield, tg = 1.853 min) as a lightyellow viscous oil. MS (ESI): m / z = 322.1 [M+H]* Step a): [3-(difluoromethyl)-4-pyridyl]methanol A solution of 3-(difluoromethyl)isonicotinaldehyde (CAS RN: 1211541-96-6; 70 mg, 445.52 umol) and methylamine hydrochloride (CAS RN: 593-51-1; 152 mg, 2.25 mmol) in MeOH (1.25 20 mL) was stirred at 23 °C for 1 h before being treated with sodium triacetoxyborohydride (290 mg, 1.37 mmol). The mixture was stirred at 23 °C for 2 h before being poured in MeOH, washed by NH4gCl and neutralized by NaOH The aqueous phase was extracted with EtOAc. The combined organic layers were dried over Na2SOq and evaporated. Purification by FC (Si02, DCM / MeOH) gave the title compound (54 mg, 72% yield) as a colorless crystalline solid. MS (ESD): m / z = 160.1 25 [M+H]° Step b):[3-(difluoromethyl)-4-pyridyl]methyl-methyl-amine WO 2025 / 012296 PCT / EP2024 / 069422 - 100 - To a solution of [3-(difluoromethyl)-4-pyridyl]methanol (54 mg, 339.35 umol) in dry THF was added DIPEA (209 uL, 713.96 umol). The solution wascooled to to 0 °C before being treated with methanesulfonylchloride (66 wL, 853.02 umol). The mixture was stirred at 0°C for 1 h before being treated with a 2.0 M solution of MeNH2 (850 uL, 1.7 mmol). The mixture was stirred at 23 5 °C for 4h, after which additional 2.0 M solution of MeNH2 (850 uL, 1.7 mmol) was added. The mixture was heated to 60 °C for 18 h before being poured onto EtOAc (20 mL) and washed with water and brine. The combined organic layers were dried over Na2SOu and evaporated. Purification by FC (Si02, DCM / MeOH) gave the title compound (44 mg, 72% yield) as a light yellow liquid. MS (ESI): m / z = 173.1 [M+H]* 10 Example 53 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutylJurea or 3-[(3R)- 4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea F F a wane oA woxn Nw | oH Nx | oH To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 15 165.22 mg, 1.04 mmol) in DMF (0.500 mL) were addedDIPEA (0.45 mL, 2.59 mmol) and CDT (220.93 mg, 1.35 mmol). The mixture was stirred at 50 °C for 1 h before being treated with N- methyl-1-(4-pyridyl)cyclobutanamine (CAS RN: 1500790-86-2; 210.0 mg, 1.04 mmol). The mixture was then heated at 80 °C for 2 h and then at 23 °C 18 h. Purification by RP-HPLC gave 167 mg of the racemic mixture. Further separation by chiral HPLC (Column chiral IF, 5 um, 250 20 x21 mm, Hexane / IPA / MeORH) gave the title compound (61.8 mg, 19% yield, tg = 11.89 min) as a light brown oil. MS (ESI): m / z = 312.2 [M+H]" Example 54 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(1H-pyrazol-5-yl)-4-pyridyl]methyl]urea —N : NH NN O F JAS “a | N N Nx | oH WO 2025 / 012296 PCT / EP2024 / 069422 - 101 - Under argon, to a solution of 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]-4-pyridyl]methyl]urea and 3-(4,4- difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[2-(2-trimethylsilylethoxymethy])pyrazol-3-yl]-4-pyridyl]methyl]urea (14.76 mg, 29.04 umol) in DCM (232.99 uL) was added TFA (11.19 uL, 5 145.21 umol). The mixture was stirred at 23 °C for 1.5 h after which additional TFA (33.56 uL, 435.62 umol) was added. The mixture was stirred at 23 °C for 3.5 h, after which additional TFA (11.19 uL, 145.21 pmol) was added. The mixture was stirred at 23 °C for 1 h, after which additional TFA (9.6 uL, 124.65 mol) was added and the mixture stirred at 23 °C for 2 h, after which additional TFA (44.75 uL, 580.83 umol) was added. The mixture was stirred at 23 °C for 3 10 hand then concentrated in vacuo. Purification by FC(Si02, heptane / EtOAc / EtOH) gave the title compound as a racemic mixture (9.69 mg, 99% yield) and as a white solid. MS (ESI): m / z = 338.2 [M+H]* Step a): trimethyl-[2-[[5-(4, 4, 5,5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyrazol-1- yl]methoxy Jethyl]silane and trimethyl-[3-[[5-(4, 4,5,5-tetramethyl-1, 3, 2-dioxaborolan-2- 15 yl)pyrazol-1-yl]methoxy]ethyl]silane Under argon, to a solutionof 1H-pyrazole-5-boronic acid pinacol ester (CAS RN: 844501-71-9; 300 mg, 1.55 mmol) in THF, extra dry (3 mL) was added NaH 60% in mineral oil (68.03 mg, 1.7 mmol) at 0 °C. The mixture was left stirring at 23 °C for 90 min before being treated with 2- (trimethylsilyl)ethoxymethyl chloride (329.06 wL, 1.86 mmol) at 0 °C. The mixture was stirred at 20 23 °C for 28 h before being quenched with water, extracted with EtOAc and washed with brine. The combined organic layers were dried over MgSOx and evaporated to give the title compound as a mixture of two pyrazole regioisomers (766.45 mg, quant.) as a yellow oil. The crude was directly engaged in the next transformation. MS (ESI): m / z = 243.2 [M+H-(CH3)2C-C(CHs3)2]* Step b): 3-(4,4-difluorotetrahydrofuran-3-yl)- 1-methyl-1-[[3-[2-(2- 25. trimethylsilylethoxymethyl)pyrazol-3-yl]-4-pyridyl methyl ]urea and 3-(4,4- difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[3-(2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4- pyridyl]methyl]urea In a vial underargon, trimethyl-[2-[[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1- yl]methoxy]ethyl]silane (56.32 mg, 128.51 mol), Cs2CO3 (125.62 mg, 385.54 nmol), cataC Xium 30 =Pd G4 (9.54 mg, 12.85 umol) and / - / (3-bromo-4-pyridyl)methyl]-3-(4, 4-difluorotetrahydrofuran- 3-yl)-1-methyl-urea from Example 28 (50 mg, 128.51 mol) were suspended in 1,4-dioxane (321 WO 2025 / 012296 PCT / EP2024 / 069422 - 102 - uL) and water (321 uL). The mixture was stirred at 100 °C for 3 h before being poured in EtOAc, filtered over celite and evaporated. Purification by FC (SiO2, heptane / EtOAc / EtOH) gave the title compound as a mixture of two pyrazole regioisomers (14.76 mg, 22% yield) and as a colorless oil. MS (ESI): m / z = 468.4 [M+H]* 5 Example 55 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl) ethyl]-1-methyl-urea or 3-[(3R)-4,4-difluorotetrahydrofurapyrimidin-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl) ethyl]-1- methyl-urea or3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-2-hydroxy-1-(4- pyridyl) ethyl]-1-methyl-urea or 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1- 10 (4-pyridyl)ethyl]-1-methyl-urea F F HO O ce HOL O ce : O : O 2 ) yan or 2 ) oan or Nx | oH Nx | oH F F HO oF pe HO O ae: a wdn or a yon Nx | oH Nx | oH To a solution of the diasteromeric mixture of 1-[2-[tert-butyl(dimethyl)silyl]oxy-1-(4- pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea (48.6 mg, 0.111 mmol) in DCM (250 uL) was added TFA (42.8 wL, 555.53 mol). The reaction mixture was stirred at 23 15 °C over 1 h, before being evaporated. Purification by FC (Si02, DCM / MeOH) gave the title compound as a diasteromeric mixture. Starting from the diasteromeric mixture, chiral SFC (Column chiral Amyl, 5 um, 250 x 20 mm, 15 %MeOH) gave the title compound (3.4 mg, 9.55%, tr = 3.972 min) as a colorless oil. MS (ESD: m / z = 284.1 [M+H]* 20. Step a): tert-butyl N-[2-hydroxy-1-(4-pyridyl) ethyl] carbamate To asolution of 2-amino-2-(4-pyridyl)ethanol (CAS RN: 100-43-6; 25.0 g, 180.94 mmol) in MeOH (700 mL) were added TEA (75.66 mL, 542.81 mmol) and Boc20 (39.49 g, 180.94 mmol). WO 2025 / 012296 PCT / EP2024 / 069422 - 103 - The mixture was stirred at 25 °C for 2 h. Purification by FC (PE / EtOAc) gave the title compound as a racemic mixture (22.3 g, 52% yield) and as a white solid. MS (ESI): m / z = 239.0 [M+H]* Step b): tert-butyl N-[2-[tert-butyl(dimethyl) si yl]oxy-1-(4-pyridyDethyl]carbamate To a solution of tert-butyl N-[2-hydroxy-1-(4-pyridyl)ethyl]carbamate (750.0 mg, 3.15 mmol) in 5 DCM (20 mL) were added 1H-imidazole (535.38 mg, 7.87 mmol) and tert-butyl-chloro- dimethylsilane (1181.54 mg, 7.87 mmol). The mixture was stirred at 20 °C for 16 h. Purification by FC (PE / EtOAc) gave the title compound as a racemic mixture (1090.0 mg, 98% yield) and as white solid. MS (ESI): m / z = 353.1 [M+H]* Step c): tert-butyl N-[2-[tert-butyl(dimethy])silyl]oxy-1-(4-pyridy) ethyl]-N-methyl-carbamic 10 acidtert-butyl ester To a solution of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]carbamate (100 mg, 283.66 nmol) in DMF (3 mL) was added NaH 60% in mineral oil (13.62 mg, 567.31 umol) at 0°C. The mixture was stirred at 0° C for 30 min before being treated with iodomethane (35.47 uL, 567.31 umol). The mixture was stirred at 0 °C for 45min before being poured in EtOAc and 15 washed with water and brine. The combined organic layers were dried over MgSO, and evaporated. Purification by FC (SiO2, heptane / EtOAc) gave the title compound as a racemic mixture (91 mg, 83% yield) and as a yellow liquid. MS (ESI): m / z = 367.3 [M+H]" Step da): — [2-[tert-butyl(dimethyl)silyl]oxy-1-(4-pyridylethyl]-methyl-amine. 1:1 2,2,2- trifluoroacetic acid 20 To a solution of tert-butyl N-[2-[tert-butyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]-N-methyl- carbamic acid tert-butyl ester (91 mg, 0.236 mmol) in DCM (1.2 mL) was added TFA (134.45 mg, 90.84 uL, 1.18 mmol). The mixture was stirred at 23°C over 1.8 h, then concentrated under vacuo to give the title compound as a racemic mixture (123.9 mg, 97%, 70% purity) and as a light yellow liquid which was directly used to the next step without further purification. MS (ESD): m / z = 267.3 25 [M+H]° Step e): 1-[2-[tert-butyl(dimethyl)silyl]oxy-1-(4-pyridyl)ethyl]-3-(4, 4-difluorotetrahydrofuran-3- yl)-1-methyl-urea To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 60.54 mg, 384.16 umol) in DCM (1 mL) were added DIPEA (268.37 pL, 1.54 mmol) and CDT WO 2025 / 012296 PCT / EP2024 / 069422 - 104 - (75.66 mg, 460.99 umol). The mixture was stirred at 23 °C for 1 h before being treated with [2- [tert-butyl(dimethy])silyl]oxy-1-(4-pyridyl)ethyl]-methyl-amine 1:1 TFA (208.8 mg, 384.16 umol) in DCM (1 mL) and DMF (100 uL). The mixture was stirred at 23 °C over 17 h, before being evaporated. Purification by FC (SiOz, DCM / MeOH) gave the title compound as a 5 diasteromeric mixture (48.6 mg, 29% yield) and as alight yellow oil. MS (ESI): m / z = 416.3 [M+H]" Example 56 3-[3-(difluoromethyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethylJurea 2~-™~N-~N F or NN 10 To a solution of [3-(difluoromethyl)tetrahydrofuran-3-yl]amine;hydrochloride (CAS RN: 2742653-30-9; 76.48 mg, 440.56 umol) in DMF (2.2 mL) were added DIPEA (307.77 uL, 1.76 mmol) and CDT (79.54 mg, 484.62 umol). The mixture was stirred at 75 °C for 1h before being treated with methyl-[(1S)-1-(4-pyridylethyl]amine (CAS RN: 42732-16-1; 60 mg, 440.56 pmol). The mixture was stirred at 75 °C for 16 h. Purification by RP-HPLC gave the title compound as a 15 diasteromeric mixture (73.2 mg, 53% yield) and as a colorless gum. MS (ESI): m / z = 298.2 [M- Hy] Example 57 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl) methyl]urea or 3- [GR)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methylJurea F F a yon or os An Nw | oH Nw | oH 20 In a vial under argon, benzeneboronic acid, pinacol ester(34.2 mg, 162.78 umol), Cs2CO3 (159.11 mg, 488.35 pmol), cataC Xium Pd G4 (12.08 mg, 16.27 umol) and / - / (3-bromo-4-pyridyl) methyl ]- 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-urea from Example 28 (60 mg, 162.78 umol) were WO 2025 / 012296 PCT / EP2024 / 069422 - 105 - suspended in 1,4-dioxane (405 uL) and water (405 uL). The mixture was stirred at 100 °C for 4h before being poured in EtOAc, filtered over celite and concentrated in vacuo. Purification by FC (Si02, heptane / EtOAc / EtOH) gave the title compound as a racemic mixture (45.13 mg, 80% yield) and as an off-white oil. MS (ESI): m / z = 348.2 [M+H]* 5 Starting from 45.13 mg of diasteromeric mixture, chiral SFC (Column chiral OZ, 5 um, 250 x 20 mm, 20 % MeOH) gave the title compound (24.29 mg, 54% yield, tg = 1.953 min) as a white solid. MS (ESI): m / z = 348.2 [M+H]* Example 58 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]thiourea F _osf ao | N N Nx | oH 10 To a solution of4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 117.16 mg, 734.27 umol) in DCM, extra dry (2.38 mL) were added DIPEA (384.72 uL, 2.2 mmol) and 1,1'-thiocarbonyldiimidazole (143.94 mg, 807.7 umol). The mixture was stirred at 23 °C for 30 min before being treated with methyl-[(1S)-1-(4-pyridyl)ethylJamine (CAS RN: 42732-16-1; 15 100 mg, 734.27 umol). The mixture was stirred at 23 °C for 16 h before being poured in MeOH and evaporated. Purification by FC (SiO2, DCM / MeOH) gave the title compound as a diasteromeric mixture (25.1 mg, 10.89% yield) and as a light yellow oil. MS (ESD): m / z = 302.2 [M+H]" Example 59 20 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(3-methyl-1H-pyrazol-5-yl)-4- pyridyl]methyl]urea =N : NH NN oF JAAS? a | N N Nw | oH WO 2025 / 012296 PCT / EP2024 / 069422 - 106 - Under argon, to a solution of 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[5-methyl-2- (2-trimethylsilylethoxymethyl)pyrazol-3-yl]-4-pyridyl]methylJurea and 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[5-methyl-1-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]-4-pyridyl]methyl]urea (41.87 mg, 0.080 mmol in 5 DCM, extra dry (400 pL) was added TFA (123.24 uL, 1.6 mmol). The mixture was stirred at 23 °C for 4h after which additional TFA (61.62 wL, 789.83 umol) was added. The mixture was stirred at 23 °C for 1.5 h after which the mixture was concentrated in vacuo. Purification by FC (Si02, heptane / EtOAc / EtOH) gave the title compound as a racemic mixture (27.68 mg, 98% yield) and as a white solid. MS (ESI): m / z = 352.2 [M+H]* 10 Step a): trimethyl-[2-[[3-methyl-5-(4, 4,5, 5-tetramethyl-1, 3,2-dioxaborolan-2-yl)pyrazol-1- yl]methoxy Jethyl]silane and trimethyl-[2-[[5-methyl-3-(4, 4, 5,5-tetramethyl-1, 3,2-dioxaborolan- 2-yl)pyrazol-1-yl]methoxy Jethyl]silane Under argon, to a solution of 1H-pyrazole-5-boronic acid pinacol ester (CAS RN: 1888441-67-5; 300 mg, 1.44 mmol) in THF, extra dry (2.5 mL) was added NaH 60% in mineral oil (63.44 mg, 15 1.586mmol) at 0 °C. The mixture was left stirring at 23 °C for 90 min before being treated with 2-(trimethylsilyl)ethoxymethyl chloride (306.87 uL, 1.73 mmol) at 0 °C. The mixture was stirred at 23 °C for 28 h before being quenched with water, extracted with EtOAc and washed with brine. The combined organic layers were dried over MgSOx and evaporated to give the title compound as a mixture of two pyrazole regioisomers (437.06 mg, 79% yield) as a colorless oil. The crude 20 was directly engaged in the next transformation. MS (ESI): m / z = 256.4 [M+H-(CH3)2C-C(CHs3)2]* Step b): 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[5-methyl-2-(2- trimethylsilylethoxymethyl)pyrazol-3-yl]-4-pyridyl]methyl]urea and 3-(4,4- difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-[5-methyl-1-(2-trimethylsilylethoxymethyl)pyrazol- 3-yl]-4-pyridyl]methyl]urea 25 In a vial under argon, trimethyl-[2-[[3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazol-1-yl]methoxy]ethyl]silane andtrimethyl-[2-[[5-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyrazol-1-yl]methoxy]ethyl]silane as the two pyrazole regioisomers (100 mg, 260.1 umol), Cs2CO3 (254.24 mg, 780.3 umol), cataCXium Pd G4 (19.3 mg, 26.01 pmol) and / - [(3-bromo-4-pyridyl)methyl ]-3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-urea from Example 30 =©28 (95.87 mg, 260.1 umol) were suspended in 1,4-dioxane (650.25 wL) and water (650.25 uL). The mixture was stirred at 100 °C for 3 h before being poured in EtOAc, filtered over celite and WO 2025 / 012296 PCT / EP2024 / 069422 - 107 - concentrated in vacuo. Purification by FC (SiO2, heptane / EtOAc / EtOH) gave the title compound as a mixture of two pyrazole regioisomers (41.87 mg, 31% yield) and as a colorless oil. MS (ESI): m / z = 482.3 [M+H]* Example 60 5 2-cyano-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(LS)-1-(4-pyridyl)ethyl]guanidine Nw F QF a | N N Nx | oH To a solution of 3-(4,4-difluorotetrahydrofuran-3-yl)-1,2-dimethyl-1-[(1S)-1-(4-pyridyl)ethyl]isothiourea (48 mg, 152.2 umol) in THF, extra dry (500 uL) was added cyanamide (63.98 mg, 1.52 mmol) at 23 °C. The mixture was stirred at 23 °C for 16 h after which further 10 DIPEA (53.16 wL, 304.39 umol) was added. The reaction was heated to 45 °C for 32 h before being concentrated under reduced pressure. Purification by FC (Si02, DCM / MeQOH) followed by RP FC (MeCN / H20) gave the title compound as a diasteromeric mixture (7.4 mg, 15% yield) and as a colorless oil. MS (ESI): m / z = 310.1 [M+H]* Step a): 3-(4,4-difluorotetrahydrofuran-3-yl)-1,2-dimethyl-1-[(1S)-1-(4-pyridyl ethyl Jisothiourea 15 To a solution of Example 58: 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4- pyridyl ethyl]thiourea (46.1 mg, 152.97 umol) in MeOH, extra dry (1 mL) at -78 °C was added dropwise iodomethane (309 uL, 4.94 mmol). The mixture was stirred at 23 °C for 16 h. before being treated with 2 M NH3 in MeOH and evaporated, to give the crude title compound (45 mg, 47% yield) as alight yellow oil which was directly used in the next step. MS (ESI): m / z = 316.1 20 [M+H]° Example 61 1-Methyl-3-(5-oxotetrahydrofuran-3-yl)-1-[(1S)-1-(4-pyridylethyl]urea Pp : O a | N N Nx | oH WO 2025 / 012296 PCT / EP2024 / 069422 - 108 - To a solution of 4-aminotetrahydrofuran-2-one;hydrochloride (CAS RN: 138846-59-0; 100 mg, 726.96 umol) in DCM (5 mL) were added DIPEA (507.85 pL, 2.91 mmol) followed by CDT (143.17 mg, 872.35 pmol), at 23 °C. The reaction mixture was stirred at 23 °C for 1 h. Then, methyl-[(1S)-1-(4-pyridyl)ethyl]Jamine;dihydrochloride (CAS RN: 42732-16-1; 152.02 mg, 5 726.96 umol) in DCM (5 mL) was added and the reaction mixture was stirred at 23 °C for 15 h. The solvent was evaporated. Purification by FC (S102; DCM / MeOH ) and by RP-HPLC (YMC- Triart C18, 12nm, 5um, 100 x 30mm, CH3CN / H20+0.1% TEA) delivered the title compound as a mixture of diasteromers (171.9 mg, 88% yield, tg = 0.825 min) and as a colorless oil. MS (ESI): m / z = 264.2 [M+H]" 10 Example 623-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]- 4-pyridyl]methyljurea or 3-[{(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3 R)- tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea or 3-[(3R)-4,4-difluorotetrahydrofuran-3- yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methylJurea or 3-[(3R)-4,4- 15 difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-][(3 R)-tetrahydrofuran-3-yl]methyl]-4- pyridyl]methyl]urea o F fe) F “ OF OF no | 4H n2 | 4H o ) F fe) F S N N S N N To a solution of 4,4-difluorotetrahydrofuran-3-amine;hydrochloride (CAS RN: 2408969-70-8; 171.45 mg, 1.07 mmol) in DCM (25 mL) were added DIPEA (0.75 mL, 4.3 mmol) followed by 20 CDT (193.99 mg, 1.18 mmol). The reaction mixture was stirred at 23 °C for 2 h, before being treated with N-methyl-1-[3-(tetrahydrofuran-3-ylmethyl)-4- pyridyl]methanamine;dihydrochloride (300.0 mg, 1.07 mmol). The mixture was stirred at 23 °C for 20 h before being treated withwater. The aqueous layer was back-extracted three times with DCM. The organic layers were dried over Na2SO4 and evaporated. Purification by RP-HPLC WO 2025 / 012296 PCT / EP2024 / 069422 - 109 - (XBridge BEH C18, 100 x 19mm, 5 uM, MeCN / H20+0.1% HCl) and chiral SFC (Column Chiralpak IF, 250x20 mm, 5 um, 25% / 25% IPA / MeOH) delivered the title compound (16.5 mg, 4% yield, tg = 21.23 min) as a yellow oil. MS (ESI): m / z = 356.2 [M+H]* Step a: tert-butyl N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamate 5 Boc2O (7.16 g, 32.82 mmol) was added dropwise to a solution of 1-(3-bromo-4-pyridyl)-N- methyl-methanamine (CAS RN: 73335-64-5; 6.0 g, 29.84 mmol) in DCM (30 mL) at 25 °C. After stirring for 18 h, the solvent was evaporated to give the title compound (9.0 g, 96% yield) as a light yellow oil. MS (ESI): m / z = 303.0 [M+H]* Step 6: tert-butyl N-methyl-N-[[3-[(F)-tetrahydrofuran-3-ylidenemethyl]-4-pyridyl]methyl] 10 carbamate In a vial under argon,4,4,5,5-tetramethyl-2-[(Z)-tetrahydrofuran-3-ylidenemethyl]-1,3,2- dioxaborolane (CAS RN: 2365173-52-8; 800.0 mg, 3.81 mmol), tert-butyl N-[(3-bromo-4- pyridyl)methyl]-N-methyl-carbamate (1.147 g, 3.81 mmol), K2CO3 (1.053 g, 7.62 mmol) and (PPh3)2PdClz2: DCM complex (466.11 mg, 0.57 mmol) were suspended in 1,4-dioxane (32 mL) and 15 water (8 mL). The mixture was sparged with Argon for 10 min and then stirred vigorously at 90 °C for 16 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiOz; PE / THF) delivered the title compound (760 mg, 60% yield) as a light brown solid. MS (ESI): m / z = 305.2 [M-Bu+H]* Step c: tert-butyl N-methyl-N-[[3-(tetrahydrofuran-3-ylmethyl)-4-pyridyl]methyl]carbamate 20 +tert-Butyl N-methyl-N-[[3-[(E)-tetrahydrofuran-3-ylidenemethy]]-4-pyridyl]methyl]carbamate (100.0 mg, 0.33 mmol) was dissolved in EtOAc (15 mL) and hydrogenated at 3800 mmHg over Pd / C 10% (14.14 mg, 0.01 mmol) for 48 h. The reaction mixturewas filtered to remove Pd / C and the solvent evaporated to deliver the title compound (100.0 mg, 93% yield) as a light yellow oil. MS (ESI): m / z = 307.2 [M+H]* 25. Step d: N-methyl-1-[3-(tetrahydrofuran-3-ylmethyl)-4-pyridyl]methanamine dihydrochloride tert-Butyl N-methyl-N-[[3-(tetrahydrofuran-3-ylmethyl)-4-pyridyl]methyl]carbamate (600.0 mg, 1.96 mmol) was dissolved in MeOH (25 mL) and HCl (4 N in 1,4-dioxane) (0.49 mL, 1.96 mmol) was added. The reaction was stirred at 25 °C for 16 h. The solvent was evaporated and the residue triturated with Et20, filtered and dried to deliver the title compound (350.0 mg, 61% yield) as a 30. yellow solid. MS (ESI): m / z = 207.2 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 - 110- Synthesis of the most common intermediate 1- / (3-bromo-4-pyridyl) methyl]-3-[(3S)-4,4- difluorotetrahydrofuran-3-yl]-1-methyl-urea Int-1 for Examples 63, 64, 65, 66, 67, 70 and 74 F Br OF Bw? a | N N* Nw | oH To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride(CAS RN: 2408969-70-8; 5 474.78 mg, 2.98 mmol) in DCM (7 mL) were added DIPEA (1.56 mL, 8.93 mmol) followed by CDT (732.54 mg, 4.46 mmol). The mixture was stirred at 23 °C for 2 h. Then, 1-(3-bromopyridin- 4-yl)-n-methylmethanamine (CAS RN: 463941-58-4; 418.08 nL, 2.98 mmol) was added. The reaction mixture was stirred at 23 °C for 20 h before being treated with water. The aqueous layer was back-extracted three times with DCM. The organic layers were dried over Na2SO.4 and 10 evaporated. Purification by FC (SiOz; EtOAc / EtOH / Heptane) and by chiral SFC (Column Chiralpak IF, 250x20 mm, 5 um, 26% MeOH) delivered the title compound (383.43 mg, 49% yield, tk = 1.512 min) as an off-white semisolid. MS (ESI): m / z = 352.0 [M+H]* Example 63 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(4-pyridyl)-4-pyridyl]methyl]urea ZN | F S OF JwK S ao | N N™ Nw | oH 15 In a vial under argon, 1-[(3-bromo-4-pyridyl)methy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea Int-1 (63.91 mg,182.5 umol), pyridine-4-boronic acid, pinacol ester (CAS RN: 181219-01-2; 41.17 mg, 200.75 umol), Cs2CO3 (178.39 mg, 547.51 mol) and cataC Xium Pd G4 (13.55 mg, 18.25 umol) were suspended in 1,4-dioxane (456.26 wL) and water (456.26 uL). The 20 reaction mixture was sparged with Argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (Si0O2; EtOAc / EtOH / Heptane) delivered the title compound (39.78 mg, 61% yield) as a white solid. MS (ESI): m / z = 349.2 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 -lll- Example 64 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(3-pyridyl)-4-pyridyl]methyl]urea N~ | F S OF ao | N N™ Nx | oH In a vial under argon, 1-[(3-bromo-4-pyridyl)methy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 5 1-methyl-urea Int-1 (63.91 mg, 182.5 pmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (CAS RN: 329214-79-1; 41.17 mg, 200.75 umol), Cs2xCO3(178.39 mg, 547.51 wmol) and cataCXium Pd G4 (13.55 mg, 18.25 umol) were suspended in 1,4-dioxane (456.26 uL) and water (456.26 uL). The mixture was sparged with Argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and 10 evaporated. Purification by FC (SiOz; EtOAc / EtOH / Heptane) delivered the title compound (43.08 mg, 68% yield) as a white solid. MS (ESI): m / z 349.2 [M+H]" Example 65 1-[[3-(4-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea Cl F OF J wK a | N N“ Nw | oH 15 In a vial under argon, 1-[(3-bromo-4-pyridyl)methy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea Int-1 (63.91 mg, 182.5 mol), 4-chlorophenylboronic acid (CAS RN: 1679-18-1; 31.39 mg, 200.75 umol), Cs2CO3 (178.39 mg, 547.51 umol) and cataCXium Pd G4 (13.55 mg, 18.25 mol) were suspended in 1,4-dioxane (456.26 wL) and water (456.26 uL). The reaction 20 mixture was sparged with Argon for 10min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by RP (C18, MeCN / H20) delivered the title compound (19.31 mg, 28% yield) as a white solid. MS (ESD): m / z = 382.1 [M+H]" WO 2025 / 012296 PCT / EP2024 / 069422 -112- Example 66 1-[[3-(2-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea F Cl OF Bw 9 oO | N N™ Nx | oH 5 Ina vial under argon, 1-[(3-bromo-4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea Int-1 (63.91 mg, 182.5 mol), 2-chlorophenylboronic acid (CAS RN: 3900-89-8; 41.17 mg, 200.75 umol), Cs2xCO3 (178.39 mg, 547.51 umol) and cataCXium Pd G4 (13.55 mg, 18.25 umol) were suspended in 1,4-dioxane (456.26 wL) and water (456.26 uL). The mixture was sparged with Argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 10 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC(SiOz; EtOAc / EtOH / Heptane) delivered the title compound (46.94 mg, 67% yield) as a white solid. MS (ESI): m / z 382.1 [M+H]* Example 67 1-[[3-(3-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- 15 urea Cl F OF oO | N N™ Nw | oH In a vial under Argon, 1-[(3-bromo-4-pyridyl)methy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea Int-1 (63.91 mg, 182.5 umol), 3-chlorophenylboronic acid (CAS RN: 63503-60-6; 31.39 mg, 200.75 umol), Cs2CO3 (178.39 mg, 547.51 umol) and cataCXium Pd G4 (13.55 mg, 20 18.25 umol) were suspended in 1,4-dioxane (456.26 wL) and water (456.26 uL). The reaction mixture was sparged with Argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by RP WO 2025 / 012296 PCT / EP2024 / 069422 -113- (C18, MeCN / H20) delivered the title compound (30.25 mg, 43% yield) as a white solid. MS (ESD): m / z = 382.1 [M+H]" Example 681-[2-(3-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea : Cl F ° OF ee “a | N N Nw | 4H 5 To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 26.67 mg, 167.15 umol) in DCM (840 pL) were added DIPEA (190.75 uL, 1.11 mmol) followed by CDT (35.56 mg, 216.7 umol). The mixture was stirred at 23 °C for for 2 h. Then, [2-@- chlorophenoxy)-1-(4-pyridylethyl]-methyl-amine;hydrochloride (50 mg, 167.11 pumol) was 10 added. The reaction mixture was stirred at 23 °C for 16 h. The organic layers were dried over NazSOx4 and evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12nm, 5um, 100 x 30mm, CH3CN / H20+0.1% HCOOH) delivered the title compound as a diasteromeric mixture (13 mg, 19% yield) and as an off-white semisolid. MS (ESI): m / z = 412.2 [M+H]" Step a: 2-(3-chlorophenoxy)-1-(4-pyridyl)ethanone 15 Toa solution of 3-chlorophenol (CAS RN: 108-43-0; 22.65 g, 176.19 mmol) in MeCN (150 mL) was added K2COs(24.35 g, 176.19 mmol) at 25 °C. 4-(Bromoacetyl)pyridine hydrobromide (CAS RN: 5349-17-7; 3.0 g, 10.68 mmol) was then added and the reaction stirred for 0.15 hat 60 °C. A second portion of 4-(bromoacetyl)pyridine hydrobromide (CAS RN: 5349-17-7; 5.0 g, 17.8 mmol) was then added and the reaction stirred for further 0.15 h at 60 °C. A third portion of 4- 20 (bromoacetyl)pyridine hydrobromide (CAS RN: 5349-17-7; 8.0 g, 28.48 mmol) was then added and the reaction stirred for further 30 min at 60 °C. The solvent was evaporated. Purification by FC (SiO2; PE / EtOAc) delivered the title compound (10.76 g, 74%, yield) as a pink solid. MS (ESI): m / z = 248.0 [M+H]" Step b: 2-(3-chlorophenoxy)-N-methyl-1-(4-pyridyl)ethanamine dihydrochloride WO 2025 / 012296 PCT / EP2024 / 069422 -114- A mixture of 2-(3-chlorophenoxy)-1-(4-pyridyl)ethanone (2.0 g, 8.07 mmol), MeNH2:HCl (CAS RN: 593-51-1; 1.09 g, 16.15 mmol), NaOAc (1.373 g, 20.19 mmol) in DCE (20 mL) was stirred at 70 °C for 2 h. To the reaction wasadded NaBH3CN (1.526 g, 24.22 mmol) and the resulting mixture was stirred at 25 °C for 12 h. The precipitate was filtered off and the filtrate evaporated. 5 Purification by RP-HPLC (Phenomenex Luna C18, 15um, 150 x 40mm, CH3CN / H20+0.1% HCO2H) and titration with HCI delivered the title compound (253.11 mg, 12% yield) as a yellow solid. MS (ESI): m / z = 263.1 [M-2HCI+H]* Example 69 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-prop-1-ynyl-4-pyridyl) methyl]urea I i ie. a N* *~N n J | 4 10 In a vial under argon, bis(triphenylphosphine)palladium (II) chloride (3.06 mg, 4.36 umol), TEA (91.21 pL, 654.39 pmol) and 1-[(3-bromo-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3- yl)-1-methyl-urea (80.4 mg, 0.218 mmol) were dissolved in THF extra dry (1.09 mL). 1 M Prop- 1-yne solution (261.75 uwL, 261.75 pmol) and Cul (1.66 mg, 8.73 mol) were then added and the 15 mixture heated to 65 °C. After 1.5 h, further 1 M prop-1-yne solution (218.13 wL, 218.13 umol) was added and the mixtureheated to 65 °C. After 4.5 h, further 1 M prop-1-yne solution (436.26 uL, 436.26 umol) was added and the mixture heated to 65 °C. After 25 h, further 1 M prop-1-yne solution (436.26 uL, 436.26 wumol) was added. After 26 4h, _ further bis(triphenylphosphine)palladium (II) chloride (15.31 mg, 21.81 umol), Cul (8.31 mg, 43.63 20 umol), TEA (91.21 uL, 654.39 umol ) and 1 M prop-1-yne solution (436.26 uL, 436.26 umol) were added. The reaction mixture was filtered through a celite pad and washed with EtOAc. The combined filtrate was evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12nm, 5um, 100 x 30mm, CH3CN / H20+0.1% HCOOH) delivered the title compound (1.1 mg, 2% yield) as a light yellow oil. MS (ESI): m / z = 310.1 [M+H]* 25. Step a: 1-[(3-bromo-4-pyridyl) methyl]-3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-urea To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 39.68 mg, 248.68 nmol) in DCM (800 pL) were added DIPEA (130 uL,746.05 umol) followed WO 2025 / 012296 PCT / EP2024 / 069422 -115- by CDT (44.9 mg, 273.55 umol). The reaction mixture was stirred at 23 °C for 16 h. Then, 1-(- bromopyridin-4-yl)-n-methylmethanamine (CAS RN: 463941-58-4; 50 mg, 248.68 mol) was added. The reaction mixture was stirred at 23 °C for 4 h. MeOH and Isolute were added. The organic layers were dried over Na2SO4 and evaporated. Purification by FC (S102; DCM / MeOH) 5 delivered the title compound (80.4 mg, 88% yield) as a colorless oil. Example 70 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(2-pyridyl)-4-pyridyl]methyl]urea a ) FE Nw OF Pe a | yn " Nw | oH In a vial under Argon, 1-[(3-bromo-4-pyridyl)methy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 10 1-methyl-urea Int-1 (30.47 mg, 87.02 umol), 2-tri-n-butylstannylpyridine (CAS RN: 17997-47-6; 69.64 = uL, 174.03 umol) and LiCl (7.38 mg, 174.03 umol) and tetrakis(triphenylphosphine)palladium (20.11 mg, 17.4 umol) were suspended in 1,4-dioxane (1.5 mL). The mixture wassparged with Argon for 10 min and then stirred vigorously at 100 °C for 15 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification 15 by RP (C18, MeCN:H20) and FC (Si02; EtOAc / EtOH / Heptane) delivered the title compound (5.79 mg, 19% yield) as a white solid. MS (ESI): m / z = 349.1 [M+H]* Example 71 1-[2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea Cl F ° se: a | yAN Nw | oH 20 Toasolution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 30.37 mg, 190.35 umol) in DCM (956 uL) were added DIPEA (217.23 wL, 1.27 mmol) followed WO 2025 / 012296 PCT / EP2024 / 069422 - 116- by CDT (40.5 mg, 246.75 umol). The reaction mixture was stirred at 23 °C for 1 h. Then, [2-(4- chlorophenoxy)-1-(4-pyridyl)ethyl]-methyl-amine (50 mg, 190.31 mol) was added. The reaction mixture was stirred at 23 °C for 16 h. The organic layers were dried over Na2SOu4 and evaporated. Purification by RP-HPLC(Phenomenex Gemini NX C18, 12nm, 5um, 100 x 30mm, 5 CH3CN / H20+0.1% HCOOH) delivered the title compound as a diasteromeric mixture (23 mg, 29% yield) and as a white powder. MS (ESI): m / z = 412.1 [M+H]* Step a: 2-(4-chlorophenoxy)-1-(4-pyridyl)ethanone To a solution of 4-chlorophenol (CAS RN: 106-48-9; 2.75 g, 21.36 mmol) in MeCN (10 mL) was added K2CO3 (6.18 g, 44.5 mmol) at 25 °C. 4-(bromoacetyl)pyridine hydrobromide (CAS RN: 10 5349-17-7; 5.0 g, 17.8 mmol) was then added and the reaction stirred at 25 °C for 12 h. The solvent was evaporated. Purification by RP-HPLC (CH3CN / H20+0.1% NH3.H20) delivered the title compound (3.0 g, 68% yield) as a white solid. MS (ESI): m / z = 248.6 [M+H]* Step b: 2-(4-chlorophenoxy)-N-methyl-1-(4-pyridylethanamine A mixture of 2-(4-chlorophenoxy)-1-(4-pyridyl)ethanone (3.0 g, 12.11 mmol), MeNH2.HCI (CAS 15 RN: 593-51-1; 1.7 g, 24.22 mmol), NaOAc (2.06 g, 30.28 mmol) in DCE (20 mL) was stirred at 70°C for 2 h. To the reaction was added NaBH3CN (2.29 g, 36.34mmol) and the resulting mixture was stirred at 25 °C for 12 h. The precipitate was filtered off and the filtrate was evaporated. Purification by RP-HPLC (CH3CN / H20+0.1% TEA) and trituration with HCl delivered the title compound (590.66 mg, 18% yield) as a yellow solid. MS (ESI): m / z = 263.2 [M+H]* 20 Example 72 3-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea or 3- [GR,4S)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl) ethyl]urea HO HO - or - Za i at Za i wAn Nw | oH Nw | oH To a solution of (trans-4-amino-tetrahydrofuran-3-ol (CAS RN: 330975-13-8; 57.55 mg, 558.04 25 wumol) in DMF (1.12 mL) were added DIPEA (382.11 wL, 2.23 mmol) and TMSCI (72.78 uL, 558.04 nmol). The reaction was stirred at 23 °C for 30 min, before being treated with CDT (137.38 mg, 837.07 pmol). The reaction mixture was stirred at 75 °C for 40 min. Then, methyl-[(1S)-1-(4- WO 2025 / 012296 PCT / EP2024 / 069422 - 117- pyridyl)ethyl]Jamine (CAS RN: 42732-16-1; 80 mg, 558.04mol) was added. The mixture was stirred at 75 °C for 16 h. The organic layers were dried over Naz2SOq and evaporated. Purification by RP (C18, CH3CN / H20) and chiral SFC (Column chiral Amy1, 5 um, 250x20 mm, 28% MeOH) gave the title compound (8.7 mg, 6% yield, tp = 3.695 min) as a light brown solid. MS (ESI): m / z 5 = 266.2 [M+H]* Example 73 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4- pyridyl]methyl]urea or 3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3- (tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]urea ° F ° F OF OF n J | 4 n J | 4 10 To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 166.3 mg, 1.04 mmol) in DCM (5 mL) were added DIPEA (910 pL, 5.21 mmol) followed by CDT (205.2 mg, 1.25 mmol). The reaction mixture was stirred at 23 °C for 40 min. Then, methyl-[[3- (tetrahydropyran-4-ylmethy])-4-pyridyl]methyl]amine.2,2,2-trifluoroacetic acid (1.16 g, 1.04 15 mmol) was added. The reactionmixture was stirred at 23 °C for 16 h. The organic layers were dried over Na2SOz, mixed with Isolute and evaporated. Purification by FC (SiOz; DCM / MeOH) and by chiral SFC (Chiral column OZ-H, S5um, 250 x 20 mm, 25% MeOH) delivered the title compound (24.9 mg, 6% yield, tr = 1.780 min) as a yellow gum. MS (ESI): m / z = 370.2 [M+H]* Step a: N-[(3-bromo-4-pyridyl) methyl]-N-methyl-carbamic acid tert-butyl ester 20 To a solution of (3-bromo-4-pyridyl)methyl-methyl-amine (CAS RN: 463941-58-4; 2500 mg, 12.43 mmol) in DCM (60 mL) was added DIPEA (8.69 mL, 49.74 mmol), followed by the addition of Boc20 (4.33 mL, 18.65 mmol), at 23 °C. The mixture was for 17 h at this temperature, before being treated with water and diluted with DCM. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and 25 evaporated. Purification by FC (SiO2; heptane / EtOAc), to give the title compound (3078 mg, 80.55%) as an orange oil. MS(ESI): m / z = 301.1 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 - 118- Step b: N-methyl-N-[[3-(tetrahydropyran-4-ylidenemethyl)-4-pyridyl]methyl]carbamic acid tert- butyl ester To a solution of N-[(3-bromo-4-pyridyl)methyl]-N-methyl-carbamic acid tert-butyl ester (500 mg, 1.63 mmol) and 4,4,5,5-tetramethyl-2-(tetrahydropyran-4-ylidenemethyl)-1,3,2-dioxaborolane 5 (364.6 mg, 1.63 mmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was added K2CO3 (674.58 mg, 488 mmol) under Argon, followed by the addition of dichloro(1,1’- bis(diphenylphosphino)ferrocene)palladium (IT) (120.68 mg, 162.69 umol). The mixture was stirred for 15 hat 90 °C, before being cooled down to 23 °C, filtered, and evaporated. Purification by FC (Si02; DCM / MeOH) gave the title compound (413.8 mg, 75.89%) as an orange oil. MS 10 (ESD): m / z =319.2 [M+H]" Step c: N-methyl-N-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]carbamic acid tert-butyl ester A solution ofN-methyl-N-[[3-(tetrahydropyran-4-ylidenemethyl)-4-pyridyl]methyl]carbamic acid tert-butyl ester (515 mg, 1.54 mmol) in MeOH (8 mL) was purged with Argon, followed by 15 addition of Pd / C (163.52 mg, 153.65 umol). The system was then purged with H2. The reaction mixture was stirred for 3 h at 23 °C, before being filtered on a celite pad, washed with MeOH, and evaporated, giving the title compound (433.8 mg, 79.3%) as an orange oil. MS (ESI): m / z = 321.2 [M+H]" Step da: — methyl-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyllamine — 1:1 -2,2,2- 20 ‘trifluoroacetic acid To a solution of N-methyl-N-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]carbamic acid tert-butyl ester (433.8 mg, 1.22 mmol) in DCM (6 mL) was added TFA (938.68 uL, 12.18 mmol) at 23 °C. The mixture was stirred for 3 h at this temperature, before being treated with more TFA (469.34 uL, 6.09 mmol). The mixture was stirred for another 2 h at 23 °C before being eevaporated, 25 giving the title compound (1.16 g,85.52%) as a brown oil. MS (ES): m / z = 221.2 [M+H]" Example 74 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[4-(trifluoromethyl)phenyl]-4- pyridyl]methyl]urea WO 2025 / 012296 PCT / EP2024 / 069422 - 119- F FF F OF BK a | N N* Nw | oH In a vial under Argon, 1-[(3-bromo-4-pyridyl)methy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea Int-1 (60.0 mg, 171.35 mol), 4-(trifluoromethyl)phenylboronic acid (CAS RN: 128796-39-4; 36.91 mg, 188.49 mol), Cs2CO3 (167.49 mg, 514.05 umol) and cataCXium Pd G4 5 (12.72 mg, 17.14 umol) were suspended in 1,4-dioxane (400 uL) and water (400 uL). The mixture was sparged with Argon for 10 min and then stirred vigorously at 100 °C for 3 h. After cooling to 23 °C, the mixture was diluted with EtOAc, filtered and evaporated. Purification by FC (SiOz; EtOAc / EtOH / Heptane) delivered the title compound (48.57 mg, 68% yield) as a white solid. MS (ESI): m / z 416.0 [M+H]* 10 Example 75[3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3,5-dimethyl-4-pyridyl) ethyl]-1-methyl- urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1- methyl-urea] or [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3,5-dimethyl-4-pyridyl) ethyl]-1-methyl- 15 urea and 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1- methyl-urea] or [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3,5-dimethyl-4-pyridyl) ethyl]-1-methyl- urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1- methyl-urea] or 20 [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1- methyl-urea] or [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1 R)-1-(, 5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1- 25 methyl-urea] or WO 2025 / 012296 PCT / EP2024 / 069422 - 120- [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl- urea and 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1 R)-1-(3,5-dimethyl-4-pyridyl) ethyl]-1- methyl-urea] F F _ Oo a6 _ oO se : 1@) : \@) ZN Can ' A Nan . NK | NK | F F - oO Do fe Po a - yoke a yoke N ~ N ~ F F - oO Do fo) Ps oN yan " Z yAn Nw Nx F F “a ) Cant and a | Cart or NX! No! F F fe) Do fe) Ps Za ) Can and Za ) Nan or NK | NK | F F a Nan and a Nan NK | NK | WO 2025 / 012296 PCT / EP2024 / 069422 - 121 - To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 195 mg, 1.22 mmol) in DCM (2.5 mL) were added DIPEA (534 uL, 3.06 mmol) followed by CDT (251 mg, 1.53 mmol). The reaction mixture was stirred at 23 °C for for 2 h. Then, 1-(3,5-dimethyl- 4-pyridyl)ethyl-methyl-amine (167.3 mg, 1.02 mmol) was added. The reaction mixture was stirred 5 at 23 °Cfor 17h. The mixture was treated with H2O and extracted with EtOAc. The organic layers were dried over MgSOug, and evaporated. Purification by FC (SiOz; Heptane / EtOAc / EtOH) and by SFC (Chiral column OZ-H, 5um, 250 x 20 mm, 25% MeOH + 0.2% DIPEA) delivered the title compound as a mixture of two configurational isomers (4.34 mg, 1.32% yield, tp = 0.981 min) and as an off-white solid. MS (ESI): m / z = 314.2 [M+H]" 10 Step a: 1-(3,5-dimethyl-4-pyridyl)ethanol Under argon, to a solution of 3,5-dimethylpyridine-4-carbaldehyde (CAS RN: 201286-64-8; 150 mg, 1.11 mmol) in THF (8 mL) was added 3.4 M MeMgBr in 2-Me-THF (816.03 uL, 2.77 mmol) dropwise at -78 °C. The reaction mixture was slowly warmed up to 0 °C over 3.5 h. The reaction was quenched with sat. aq. NH4Cl solution. The aqueous phase was extracted with EtOAc. The 15 organic layers were dried over Na2SOgq and evaporated, to deliver the title compound (184.2 mg, over quant.) as a yellow solid. The crude was directly engaged in the nexttransformation without further purification. MS (ESI): m / z = 152.1 [M+H]" Step b: 4-(1-chloroethyl)-3,5-dimethyl-pyridine In a flask under Argon, to a solution of 1-(3,5-dimethyl-4-pyridyl)ethanol (184.2 mg, 1.16 mmol) 20 in DCM, extra dry (5 mL) was added SOCI2 (253.4 uL, 3.47 mmol) at 0 °C. The reaction mixture was stirred at 23 °C for 20 h. The mixture was quenched with sat. aq. NaHCOs3 and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSOa, filtered, and evaporated to deliver the title compound (261.78 mg, over quant.) as a yellow oil. The crude was directly engaged in the next transformation without further purification. MS (ESI): m / z = 170.0 25 [M+H]° Step c: 1-(3,5-dimethyl-4-pyridyl) ethyl-methyl-amine In a flask under Argon, 4-(1-chloroethyl)-3,5-dimethyl-pyridine (261.78 mg, 1.48 mmol), 2 M MeNH? in THF (888.8 pL, 1.78 mmol) and K2CO3 (409.47 mg, 2.96 mmol) were suspended in DMEF (7 mL). The mixture was stirred at 100 °C for 14 h. Thereaction was cooled to 50 °C. 30 ~=Additional 2 M MeNH2 in THF (2.96 mL, 5.93 mmol) and KI (12.3 mg, 74.07 umol) were added WO 2025 / 012296 PCT / EP2024 / 069422 - 122 - and the mixture was stirred at 50 °C for 18 h. The mixture was treated with H2O and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSOa,, filtered, and evaporated to deliver the title compound (167.3 mg, 57% yield) as a brown oil. MS (ESI): m / z = 165.2 [M+H]" 5 Example 76 1-[(1S)-1-(3-bromo-4-pyridyl) ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea or 1-[(1S)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea or 1-[(1R)-1-(3-bromo-4-pyridyl) ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea or 1-[(1R)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 10 1-methyl-urea F F Br 8 DP Bro. 9 Tr errr oF on Ay oO SS Nw F F Br 6) TD Br fa) DP an O or anrer fe) N Nx To a solution of(4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 277 mg, 1.74 mmol) in DCM (3.5 mL) were added DIPEA (758 uL, 4.34 mmol) followed by CDT (356 mg, 2.17 mmol). The reaction mixture was stirred at 23 °C for 2 h. Then, 1-(3-bromo-4- 15 pyridyl)ethyl-methyl-amine (611 mg, 1.45 mmol) was added. The reaction mixture was stirred at 23 °C for 20 h. The mixture was treated with H2O and extracted with EtOAc. The organic layers were dried over MgSOug, and evaporated. Purification by FC (SiOz; Heptane / EtOAc / EtOH) and by chiral SFC (Chiral column WhelkO1 r,r , Sum, 250 x 20 mm, 20% MeOH) delivered the title compound (4.34 mg, 1.32% yield, tg = 2.181 min) and as an off-white solid. MS (ESI): m / z = 20. 364.1 [M+H]* Step a: 1-(3-bromo-4-pyridylethyl-methyl-amine 1-(3-Bromopyridin-4-yl)ethanone (CAS RN: 111043-06-2; 325.95 wL, 2.5 mmol), 2M MeNH:2 in THF (1.5 mL, 3.00 mmol) and Ti(O'Pr)4 (740.05 wL, 2.5 mmol) were dissolved in THF, extra dry (6 mL). The mixture was stirred at23 °C for 20 h. NaBHg (283.68 mg, 7.5 mmol) was added at 0 WO 2025 / 012296 PCT / EP2024 / 069422 - 123 - °C and the mixture was stirred at 23 °C for 4.5 h. The reaction was quenched with 12 mL 25 % aq. NHsz sol. and the mixture stirred at 23 °C for 1 h. The mixture was filtered over celite and the solvent evaporated. The crude was partitioned between EtOAc and 1 M NaOH aqueous solution. The aqueous phase was extracted with EtOAc. The organic layers were dried over MgSOa and 5 evaporated, to give the title compound (610.48 mg, 58% yield) as a yellow oil. MS (ESD: m / z 215.0 [M+H]* Example 77 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea or 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl) ethyl]-3-[(3 R)-4,4- 10 difluorotetrahydrofuran-3-yl]-1-methyl-urea or 1-[(1S)-2-(4-chlorophenoxy)-1-(4- pyridyl) ethyl]-3-[(3 R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea or 1-[(1S)-2-(4- chlorophenoxy)-1-(4-pyridyl) ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea Cl Cl F O Fr ON OF : Jt re) or Z N N or “a ) N7 *N“ | | oH Cl Cl F F .@) fo) se ° fo Do @) no o| 4H i ee ee To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 15 30.37 mg, 190.35 umol) in DCM (956 pL) were added DIPEA (217 uL, 1.27 mmol) followed by CDT (40.5 mg, 247 umol). The reaction mixture was stirred at 23 °C for 1 h. Then, [2-(4- chlorophenoxy)-1-(4-pyridyl)ethyl]-methyl-amine (50.0 mg, 190 umol) was added. The reaction mixture was stirred at 23 °C for 16 h. The organic layers were dried over MgSOu, and evaporated. Purification by RP-HPLC (Phenomenex Gemini NX C18, 12nm, 5um, 100 x 30mm, WO 2025 / 012296 PCT / EP2024 / 069422 - 124- CH3CN / H20+0.1% HCOOH) and by chiral SFC (Chiral column Wrr, 5um, 250 x 20 mm, 24% MeOH+0.2% TEA) delivered the title compound (5.6 mg, 25% yield, tg = 3.069 min) and as a white powder. MS (ESI): m / z = 412.1 [M+H]* Step a: 2-(4-chlorophenoxy)-1-(4-pyridyl)ethanone 5Toasolution of 4-chlorophenol (CAS RN: 106-48-9; 2.75 g, 21.36 mmol) in MeCN (10 mL) were added K2COs (6.18 g, 44.49 mmol) and 4-(bromoacetyl)pyridine hydrobromide (CAS RN: 5349- 17-7; 5g, 17.8 mmol). The mixture was stirred at 25 °C for 12 h. The solvent was removed in vacuo. Purification by RP-HPLC (0.1% NH3.H20) delivered the title compound (3.0 g, 68% yield) as a white solid. MS (ESI): m / z = 248.6 [M+H]* 10 Step b: 2-(4-chlorophenoxy)-N-methyl-1-(4-pyridylethanamine A mixture of 2-(4-chlorophenoxy)-1-(4-pyridyl)ethanone (3.0 g, 12.11 mmol), MeNH3 HCl (1.7 g, 24.22 mmol), NaOAc (2.06 g, 30.28 mmol) in DCE (20 mL) was stirred at 70 °C for 2 h. NaBH3CN (2.29 g, 36.34 mmol) was then added. The mixture was stirred at 25 °C for 1 h. The 15 reaction was filtered and evaporated. Purification by RP-HPLC (0.1% NH3-H20) delivered the title compound (590.66 mg, 19% yield) as a brown oil. MS (ESI): m / z = 263.2 [M+H]* Example 783-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-3-(4-fluorophenyl)-1-(4-pyridyl) propyl]-1- methyl-urea or 3-[{(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4- 20 pyridyl)propyl]-1-methyl-urea or —3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4- fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea or 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]- 1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl) propyl]-1-methyl-urea WO 2025 / 012296 PCT / EP2024 / 069422 - 125 - F F F F : Jt re) or Z N7 SN or a ) N7~ *N* N | | H F F F F fe) TD fe) DP e) e) Nw | oH n J | 4 To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 102 mg, 639.26 mol) in DCM (2.3 mL) were added DIPEA (280 uL, 1.6 mmol) followed by CDT (152 mg, 926 umol). The reaction mixture was stirred at 23 °C for 1 h. Then, [3-(4- 5 fluorophenyl)-1-(4-pyridyl)propyl]-methyl-amine (150.0 mg, 614 umol) was added. The reaction mixture was stirred at 23 °C for 16 h. The organic layers weredried over MgSOu, and evaporated. Purification by FC (Si02; DCM / MeOH) and by chiral SFC (Chiral column Wrr, Sum, 250 x 20 mm, 29% EtOH) delivered the title compound (25 mg, 14% yield, tg = 3.005min) as a white powder. MS (ESI): m / z = 394.2 [M+H]* 10 Step a: N-[(E)-2-(4-fluorophenylethylideneamino]-4-methyl-benzenesulfonamide To a solution of (4-fluorophenyl)acetaldehyde (CAS RN: 1736-67-0; 3.5 g, 25.34 mmol) in MeOH (100 mL) was added 4-methylbenzenesulfonhydrazide (CAS RN: 1576-35-8; 4.8 g, 25.34 mmol) and mixture was stirred at 60 °C for 0.4 h. The mixture was evaporated. Purification by FC (S102; PE / EtOAc) delivered the title compound (7.8 g, quant.) as a yellow oil. MS (ESD): m / z = 307.0 15 [M+H]° Step b: 3-(4-fluorophenyl)-1-(4-pyridyl)propan-1-one WO 2025 / 012296 PCT / EP2024 / 069422 - 126 - To a solution of 4-pyridinecarboxaldehyde (CAS RN: 872-85-5; 1.56 mL, 16.32 mmol) in 1,4- dioxane (100 mL) were added N-[( / )-2-(4-fluorophenyl)ethylideneamino]-4-methyl- benzenesulfonamide (5.0g, 16.32 mmol) and Cs2CO3 (1.6 g, 48.96 mmol). The mixture was stirred at 110 °C for 12 h. The mixture was evaporated. Purification by FC (Si02; PE / EtOAc) delivered 5 the title compound (2.8 g, 75% yield) as a yellow oil. MS (ESI): m / z = 230.1 [M+H]* Step c: 3-(4-fluorophenyl)-N-methyl-1-(4-pyridyl)propan-1-amine dihydrochloride To a solution of 3-(4-fluorophenyl)-1-(4-pyridyl)propan-1l-one (2.8 g, 12.2 mmol) in THF (100 mL) was added AcOH (70 uL, 1.22 mmol) and the reaction was stirred at 25 °C for 15 min. MeNH2 in THF (73.28 mL, 146.56 mmol) was then added and the resulting mixture stirred at 25 °C for 4 10 h. NaBH3CN (3.8 g, 61.07 mmol) was added portionwise at 0 °C and the mixture stirred at 25 °C for 12 h. The mixture was evaporated. Purification by RP-HPLC (C18, CH3CN / H20 ) delivered the title compound (983.7 mg, 25% yield) as a yellow solid. MS (ESI): m / z = 245.1 [M+H]* Example 79 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- 15urea or 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea or 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran- 3-yl]-1-methyl-urea or 1-[(1R)-3,3-difluoro-1-(4-pyridyl) propyl]-3-[(3S)-4, 4- difluorotetrahydrofuran-3-yl]-1-methyl-urea F 1 F A F ow OF J Lo or CZ N7>N or a ) N~ ~N* N | l H F F F F F OF F OF 5 1@) A > 4 ZOLREC Nw | oH Ne ee 20 To a0 °C solution of 3,3-difluoro-N-methyl-1-(4-pyridyl)propan-1l-amine; 2,2,2-trifluoroacetic acid (0.3 g, 0.72 mmol) in DCM (25 mL) were added TEA (710 uL, 5.07 mmol) followed by CDI WO 2025 / 012296 PCT / EP2024 / 069422 - 127- (180 mg, 1.09 mmol). The reaction mixture was stirred at 25 °C for 1 h. Then, (4,4- difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 130.0 mg, 800 umol) was added. The mixture was stirred at 23 °C for 18 h. The organic layers were dried over MgSOa, and evaporated. Purification by RP-HPLC (C18 Chromatorex SMB, CH3CN / H20) and 5 bychiral HPLC (Chiralpack IG, 5um, 250 x 20 mm, Hexane / MeOH / IPA 50% / 25% / 25%) delivered the title compound (17.6 mg, 7% yield, tg = 15.46 min) as a yellow solid. MS (ESI): m / z = 336.0 [M+H]* Step a: methyl 4, 4-difluoro-2-(4-pyridyl) butanoate To a solution of bis(isopropyl)amine (4.65 mL, 33.19 mmol) in THF (60 mL) was added n-BuLi 10 1M in THF (14.34 mL, 35.84 mmol) dropwise, at 0 °C. The reaction was stirred at 0 °C for 30 min. Then, methyl 2-(pyridin-4-yl)acetate (CAS RN: 29800-89-3; 4.01 g, 26.55 mmol) in THF (60 mL) was added, at -40 °C. The mixture was stirred for 1 h at 0 °C. Afterwards, a solution of 2,2-difluoroethyl trifluoromethanesulfonate (3.87 mL, 29.2 mmol) in THF (40 ml) was added dropwise and the resulting mixture was stirred at -40 °C for 1 h. Then, the reaction was warmed 15 to 23 °C and stirred for 18 h. The mixture was poured into NH4Cl sat. aq. sol. (100 mL) and extracted by EtOAc. The organic layers were dried over Na2SOu, and evaporated. Purification by FC (SiOz;PE / EtOAc) delivered the title compound (2.3 g, 38% yield). MS (ESI): m / z = 216.2 [M+H]" Step b: 4,4-difluoro-2-(4-pyridyl) butanehydrazide 20 To solution of methyl 4,4-difluoro-2-(4-pyridyl)butanoate (2.3 g, 10.05 mmol) and hydrazine hydrate (CAS RN: 7803-57-8; 1.18 mL, 30.14 mmol) in EtOH (25 mL) was stirred at 75 °C for 18 h, before being evaporated. Purification by FC (SiO2; CH3CN / MeOH) delivered the title compound (1.18 g, 49% yield). MS (ESI): m / z = 216.2 [M+H]* Step c: tert-butyl N-[3,3-difluoro-1-(4-pyridyl)propyl]carbamate 25 4,4-Difluoro-2-(4-pyridyl)butanehydrazide (2.4 g, 11.15 mmol) was dissolved in HCI (64.0 mL, 182.6 mmol) and the solution was cooled to 0 °C. NaNO2 (2.31 g, 33.46 mmol) in H2O (12 mL) was added dropwise over 40 min. The reaction was stirred at 0 °C for 1 h. EtzO (100 mL) was added and the mixture slowly neutralized at the same temperature with NaHCO; sat. aq. sol. The organic layer was washed with water and brine, dried over Na2SOu, and evaporated. Theresidue 30 was diluted in ‘BUOH (40 mL) and heated at 82 °C for 2 h. The solvent was removed in vacuo by WO 2025 / 012296 PCT / EP2024 / 069422 - 128 - azeotropic distillation with toluene. Purification by FC (Si02; CHCl3 / CH3CN) delivered the title compound (1.1 g, 33% yield). MS (ESI): m / z = 273.2 [M+H]* Step d: tert-butyl N-[3,3-difluoro-1-(4-pyridyl) propyl ]-N-methyl-carbamate Sodium hydride (60% in mineral oil) (8.08 mg, 0.2 mmol) was added portionwise at 0 °C to a 5 solution of tert-butyl N-[3,3-difluoro-1-(4-pyridyl)propyl]carbamate (50.0 mg, 0.18 mmol) in THF (1 mL).The reaction mixture was stirred for 30 min then iodomethane (10 wL, 0.2 mmol) was added dropwise and the reaction was stirred at 23 °C for 18 h. The reaction was quenched with saturated NH4Cl sol. and extracted with EtOAc (30 mL). The organic phases were washed with water (2 x 50 mL) and brine (30 mL). The organic layers were combined, dried over Na2SOu, 10 filtered and evaporated. Purification by FC (SiOz;heptane / EtOAc) delivered the title compound (30.0 mg, 17% yield) as a dark brown viscous oil. MS (ESI): m / z = 287.2 [M+H]* Step e: [3, 3-difluoro-1-(4-pyridyl)propyl]-methyl-ammonium; 2, 2, 2-trifluoroacetate TFA (3.75 mL, 48.56 mmol) was added to a stirred solution of tert-butyl N-[3,3-difluoro-1-(4- pyridyl)propyl]-N-methyl-carbamate (0.68 g, 2.36 mmol) in DCM (7 mL) at 20 °C. The mixture 15 was then stirred at 20 °C for 18 h. The solvent was evaporated to deliver the title compound (1.3 g, 87% yield). MS (ESI): m / z = 187.2 [M+H]* Example 80 1-(difluoromethyl)-3-(4,4-difluorotetrahydrofuran-3-yl)-1-(4-pyridylmethyl)urea F OF AAS No A. 20 Ina vial under Argon, N-(4-pyridylmethyl)thioformamide (200.0 mg, 1.31 mmol) was dissolved in CH3CN (5 mL). A solution of AgOCF3 in CH3CN (3.94 mL, 3.94 mmol) was added. The mixture was stirred at 50 °C for 2 h. The resulting suspension was diluted with DCM and filtered through Celite. The filtrate was evaporated. The residue was diluted withDCM / CH3CN 1 / 1 (20 mL), filtered of through Celite and concentrated. The residue was dissolved in CH3CN (5 mL), 25 DIPEA (0.92 mL, 5.26 mmol) and (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 209.66 mg, 1.31 mmol) were added. The mixture was stirred at 20 °C for 15 WO 2025 / 012296 PCT / EP2024 / 069422 - 129- h. The solvent was evaporated. Purification by HPLC (Chromatorex 18, CH3CN / H20) delivered the title compound (15.9 mg, 4% yield) as a white solid. MS (ESI): m / z = 308.2 [M+H]* Step a: N-(4-pyridylmethyl)formamide To a solution of 4-(aminomethyl)pyridine (CAS RN: 3731-53-1; 1.00 g, 9.25 mmol) in THF (20 5 mL), (2,5-dioxopyrrolidin-1-yl) formate (CAS RN: 17592-54-0; 1.324 g, 9.25 mmol) was added portionwise at 0 °C. The mixture was stirred at 20 °C for 5 h. The mixture was evaporated. The residue was diluted with CH3CN (10 mL) and TEA (1.5 mL) was added. The precipitated solid was filtered off, and the filtrate evaporated to deliver the title compound (800.0mg, 57% yield) as a light brown oil. MS (ESI): m / z = 137.0 [M+H]* 10 Step b: N-(4-pyridylmethyl) thioformamide To a solution of N-(4-pyridylmethyl)formamide (800.0 mg, 5.88 mmol) in THF (20 mL), Lawesson reagent (CAS RN: 19172-47-5; 1.307 g, 3.23 mmol) was added in one portion. The mixture was heated at 55 °C for 15 h. The mixture was evaporated. The residue was diluted with water (10 mL) and TEA (2 mL) was added. The resulting solution was extracted with DCM (2x20 15 mL). The organic layers were dried over Na2SOua, and evaporated.. Purification by RP-HPLC (XBridge BEH C18, H20 / CH3CN+0.1% NHsOH) delivered the title compound (29.0 mg, 3% yield) as a white solid. MS (ESI): m / z = 153.0 [M+H]* Example 81 [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(LS)-1-(3-ethyl-4-pyridyl) ethyl]-1-methyl-urea 20 and = 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl- urea] or = [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea and 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]- 1-methyl-urea] or [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4- pyridyl) ethyl]-1-methyl-urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl- 25 4-pyridyl)ethyl]-1-methyl-urea] or [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(G- ethyl-4-pyridyl)ethyl]-1-methyl-urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1- (3-ethyl-4-pyridyl)ethyl]-1-methyl-urea] or [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)- 1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea and 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- [(1R)-1-G-ethyl-4-pyridyl)ethyl]-1-methyl-urea] or [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]- WO 2025 / 012296 PCT / EP2024 / 069422 - 130- 1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea and 3-[(3S)-4,4-difluorotetrahydrofuran-3- yl]-1-[(1R)-1-G-ethyl-4-pyridyl)ethyl]-1-methyl-urea F F _ 0 ae _ 0 Po ZN yon and ZN wAn or NJ | 4 noJo oH F F _ 0 Po fe)“Po a yAne and a yon r Nx | oH Nw | oH F F _ 0 “Po 0 Po ZN yy and Z An or n J | 4H n J | 4 F F ZN wAn and Z wAn r n J | 4H no) | 4 F F Z yy and ZA An or n J | 4H n oJ | 4 F F oN wAn and Z yon n J | 4H no) | 4 WO 2025 / 012296 PCT / EP2024 / 069422 - 131- To a solution of (4,4-difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 151.55 mg, 949.77 umol) in DCM (1.3 mL) were added DIPEA (581 pL, 3.2 mmol) followed by CDT (234 mg, 1.42 mmol). The reaction mixture was stirred at 23 °C for for 1 h. Then, 1-(3-ethyl- 4-pyridyl)ethyl-methyl-amine (156 mg, 950 nmol) was added. The reaction mixture was stirred at 5 23 °C for 16h. The organic layers were dried over MgSOu, and evaporated. Purification by SFC (Chiral column Wrr, 5um, 250 x 20 mm, 15% MeOH) delivered the title compound as a mixture of diastereomers (0.8 mg, 0.25% yield, tz = 1.834 min) and as a colorless oil. MS (ESD): m / z = 412.1 [M+H]* Step a: N-[1-(3-ethyl-4-pyridyl)ethyl]carbamic acid tert-butyl ester 10 Toasolution of 1-(3-ethyl-4-pyridyl)ethylamine (CAS RN: 56129-55-6; 500 mg, 3.16 mmol) in DCM (16 mL) was added TEA (1.76 mL, 12.65 mmol) followed by (Boc)20 (1.04 g, 4.74 mmol). The reaction was stirred at 23 °C for 18 h. The reaction was quenched with brine and extracted with DCM. The organic layers were dried over Na2SOu, and evaporated. Purification by FC (SiOz; DCM / MeOH) delivered the title compound (337 mg 41% yield) as an orange gum. MS (ESI): m / z 15 = 251.2 [M+H]* Step b: N-[1-(3-ethyl-4-pyridyl ethyl]-N-methyl-carbamic acid tert-butyl ester To a solution of N-[1-(3-ethyl-4-pyridyl)ethyl]carbamic acid tert-butyl ester (230 mg, 872.81 umol) in THF, extra dry (8.73 mL) was added 0.5 M KHMDS (3.49 mL, 1.75 mmol) under Argon at 0 °C and the mixture was stirred for 1 h. Then CH3I (81.86 wL, 1.31 mmol) was added and the 20 reaction stirred at 50 °C for 3 h. The solution was quenched with NH4Cl sat. sol. and extracted with DCM to deliver the title compound (253.1 mg, 88% yield, 80%purity) as a light brown oil. MS (ESI): m / z = 265.2 [M+H]* Step c: 1-(3-ethyl-4-pyridylethyl-methyl-amine To a solution of N-[1-(3-ethyl-4-pyridyl)ethyl]-N-methyl-carbamic acid tert-butyl ester (253.1 mg, 25 0.957 mmol) in DCM (4.8 mL) was added TFA (737.56 uL, 9.57 mmol). The resulting solution was stirred overnight at 23 °C. The mixture was neutralised with NaOH to pH 8 / 9. The water phase was extracted with DCM and further washed with water. The organic layers were dried over Na2SOu, and evaporated to deliver the title compound (156 mg, 79% yield, 80% purity) as a light brown oil. MS (ESI): m / z = 165.1 [M+H]* WO 2025 / 012296 PCT / EP2024 / 069422 - 132 - Example 82 3-(4, 4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2,2,2-trifluoro-1-(4-pyridyl)ethyljurea] F F PEF og AAS _ N N NI 4 | H Triphosgene (CAS RN: 32315-10-9; 74.9 mg, 0.25 mmol) was dissolved in DCM (6 mL) at 0 °C. 5 (4,4-Difluorotetrahydrofuran-3-yl)amine;hydrochloride (CAS RN: 2408969-70-8; 0.1 g, 0.63 mmol) and DIPEA (0.4 mL,2.27 mmol) were dissolved in DCM (6 ml) and added dropwise. The reaction mixture was allowed to warm up to 23 °C and stirred for 30 min. After that, the solution was cooled down to 0 °C and a solution of 2,2,2-trifluoro-N-methyl-1-(4-pyridyl)ethanamine (0.12 g, 0.63 mmol) and DIPEA (0.4 mL, 2.27 mmol) in DCM (6 mL) was added dropwise. The mixture 10 was stirred at 20 °C for 18 h. The solvent was evaporated. Purification by RP-HPLC (CROMATOREX SMB C18, CH3CN / H20) and chiral RP-HPLC (Column Chiralpak AD-H, 250x4.6 mm, 5 um, 50% / 25% / 25% Hexane / IPA / MeOH) delivered the title compound (4.2 mg, 1.47% yield) as an orange oil. MS (ESI): m / z = 340.2 [M+H]* Step a: 2,2, 2-trifluoro-N-methyl-1-(4-pyridyl)ethanamine 15 MeNH2:HCl (CAS RN: 593-51-1; 0.62 g, 9.14 mmol) and TEA (1.27 mL, 9.14 mmol) were added to a stirred solution of 2,2,2-trifluoro-1-(4-pyridyl)ethanone (0.8 g, 4.57 mmol) in THF (15 mL). The solution of Ti(O'Pr)4 (4.06 mL, 13.71 mmol) was added to the mixture. The reaction was stirredat 70 °C for 16 h. NaBHsy (0.02 g, 0.57 mmol) was added and the reaction stirred at 23 °C for 16 h. The reaction was quenched by reverse adding in NH3°H20 solution (1% in 20 mL of 20 water), extracted with EtOAc (20 mL), and filtered. The organic layers were dried over Na2SOa, and the solvent evaporated. Purification by FC (SiOz; CHCl3 / CH3CN) delivered the title compound (0.1 g, 10% yield) as a light red oil. MS (ESI): m / z = 191.2 [M+H]* Example 83 A compound of formula (I) can be used in a manner known per se as the active ingredient for the 25 production of tablets of the following composition: Per tablet WO 2025 / 012296 PCT / EP2024 / 069422 - 133 - Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg 5 Hydroxypropylmethylcellulose 20 mg 425 mg Example 84 A compound of formula (I) can be used in a manner known per se as the active ingredient for the 10 production of capsules of the following composition: Per capsule Active ingredient 100.0 mg Cornstarch 20.0 mg Lactose 95.0 mg 15 Tale 4.5 mg Magnesium stearate 0.5 mg 220.0 mg WO 2025 / 012296 PCT / EP2024 / 069422 - 134- Claims 1. Acompound of formula (1) Rib Ra pa RY R‘a pee R A Sy- R’ 6a w or a pharmaceutically acceptable salt thereof, wherein: 5 X, Y and Z are each selected from CR“ and N, provided that at most two of X, Y and Z are N; U _ isselected from O, S, and NRY; V___isacovalent bond or C(R‘)»; A is selected from 3- to 14-membered heterocyclyl, 5- to 14-membered 10 heteroaryl, Ce-Cio-aryl and C3-C10-cycloalkyl; L is selected from a covalent bond, -CH2—, and -NR!-: R’ is selected from hydrogen and C1-Co-alky]; R" _ is selected from hydrogen, C1-C¢-alkyl and cyano; each RY is independently selected from hydrogen, C1-C¢-alkyl and halo-C\-Co-alky]; 15 R“ is selected from hydrogen and C1-Co-alky]; R! is selected from hydrogen, halogen, cyano, C1-Co-alkyl, C2-Ce-alkenyl, C2-Co- alkynyl, halo-Ci-Ce-alkyl, hydroxy-Ci-Ce-alkyl, Ci-Co-alkoxy, halo-Ci-Ce- R'2 \y alkoxy, and a group il; R'* is selected from hydrogen, halogen, C1-Cs-alkyl, and halo-Ci-Ce-alkyl; 20 R” and R”? are each independently selected from hydrogen, C1-C¢-alkyl, halo-C1-Co- alkyl, Ci-Ce-alkoxy, halo-C)-Ce-alkoxy, Ci-Ce-alkyl-NH-C1-Ce-alkyl-, C3-Cio- cycloalkyl, C3-Cio-cycloalkyl-Ci-Ce-alkyl, Ce-Cio-aryl, Ce-Cio-aryl-Ci-Ce- alkyl, and R*°-O-C1-C¢-alkyl; wherein each Co-Cio-aryl and C3-C10-cycloalkyl is optionally substituted with 1-2 halogen substituents or 25 R* and R”°, taken together with the carbon atom to which they are attached, form a C3-Cio-cycloalkyl; WO 2025 / 012296 PCT / EP2024 / 069422 - 135 - R* is selected from hydrogen, C1-Co-alkyl, halo-C-Cs-alkyl, and C6-C1o-ary]; wherein said C¢-Cjo-aryl is optionally substituted with 1-2 halogen substituents; R? is selected from hydrogen, C1-Co-alkyl, halo-C-Cs-alkyl, and C3-C10- 5 cycloalkyl; R* and R® are each independently selected from hydrogen, halogen, hydroxy, C- Ce-alkyl, 5- to 14-membered heteroaryl, Ce-Cio-aryl, Ce-Cio-aroyl, 5- to 14-membered heteroaroyl; wherein said 5- to 14-membered heteroaryl, Ce-C10- aryl, C6-Cio-aroyl, 5- to 14-membered heteroaroyl are optionally substituted 10 with 1-3 substituents independently selected from halogen and hydroxy-C1-Ce- alkyl; or R* and R®, taken together with the carbon atom to which they are attached, form a C3-Cio-cycloalkyl or a 3- to 14-membered heterocyclyl, wherein said C3-Cjo0- cycloalkyl and 3- to 14-membered heterocyclyl are optionally substituted with 15 1-3 halogen substituents; or R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Ci0-cycloalkyl; R** and R°? are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a 20 C3-Cio-cycloalkyl or oxo; R° and R° are each independently selected from hydrogen, 5- to 14-membered heteroaryl, and C6-Cio-aryl; wherein said 5- to 14-membered heteroaryl, and Ce-Cio-aryl are optionally substituted with 1-3substituents independently selected from halogen, Ci-Ce-alkyl, halo-Ci-Ce-alkyl, C3-Cio-cycloalkyl, and 25 5- to 14-membered heteroaryl; and R’ _ is selected hydrogen, C1-C¢-alkyl, halo-Ci-Co-alkyl, and 5- to 14-membered heteroaryl. 2. |The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: 30 (i) Xand Y are CH and Z is CR”; wherein R% is selected from hydrogen and C)- Ce-alkyl; or (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH. WO 2025 / 012296 PCT / EP2024 / 069422 - 136 - 3. The compound of formula (1) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: (i) |X, Y are CH and Z is CR”; wherein R% is selected from hydrogen and methyl, or 5 (ii) Xand Z are CH and Y is N. 4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are CH. 5. | The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptablesalt thereof, wherein: 10 R! _ is selected from hydrogen, halogen, cyano, C1-Co-alkyl, C2-C6-alkynyl, halo- Ci-Ce-alkyl, hydroxy-C1-Ce-alkyl, Ci-Ce-alkoxy, and a group A is selected from 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms selected from N, O, and S, 5- to 6-membered heteroaryl comprising 1 to 3 15 heteroatoms selected from N, O, and S, phenyl, and C3-C¢-cycloalkyl; L is selected from a covalent bond, -CH2—, and -NR!-: R’ is hydrogen; and R!* is selected from hydrogen, halogen, C1-Co-alkyl, and halo-C1-C¢-alkyl. 6. The compound of formula (1) according to claim 5, or a pharmaceutically acceptable 20 salt thereof, wherein: R! _ is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, prop-1- ynyl, hydroxymethyl, CHF2, methoxy, and a group ; A is selected from azetidine, tetrahydrofurane, tetrahydropyrane, pyrrolidine, pyrazole, phenyl, pyridyl, and cyclopropyl; 25 L is selected from a covalent bond, -CH2—, and -NR!-: R’ is hydrogen; and R!* isselected from hydrogen, chloro, methyl, and CF3. WO 2025 / 012296 PCT / EP2024 / 069422 - 137 - 7. The compound of formula (1) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R! is selected from hydrogen, halogen, and C1-Ce-alkyl. 8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R! is selected from hydrogen, fluoro, and methyl. 5 9. The compound of formula (I) according to any one of claims | to 8, or a pharmaceutically acceptable salt thereof, wherein: R** is selected from hydrogen, C1-Co-alkyl, halo-Ci-Co-alkyl, C1-Co-alkyl-NH-C- Co-alkyl-, C3-Cio-cycloalkyl, phenyl-Ci-Cs-alkyl, and R?°-O-C-C¢-alkyl; wherein said phenyl is optionally substituted with 1 halogen substituent; 10 Ris hydrogen; and R* is selected from hydrogen, C1-C¢-alkyl, halo-Ci-C¢-alkyl, and phenyl; wherein said phenyl is optionally substituted with 1 halogen substituent; or R* and R”°, taken together with the carbon atom to which theyare attached, form a C3-Ce-cycloalkyl. 15 10. The compound of formula (1) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH2xCHF2, CH3N- CH2-, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF2-O-CHo-, CF3-O-CH2-, and cyclopropyl; and 20 R?? is hydrogen; or R* and R”°, taken together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl. 11. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein: 25 R* is Ci-Co-alkyl; and R?’ is hydrogen. 12. The compound of formula (1) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein: R* is methyl; and 30 R?> is hydrogen. WO 2025 / 012296 PCT / EP2024 / 069422 - 138 - 13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R? is selected fromC1-Co-alkyl and halo-C1-Ce-alkyl. 14. The compound of formula (I) according to any one of claims 1 to 12, or a 5 pharmaceutically acceptable salt thereof, wherein R? is selected from methyl and CHF». 15. The compound of formula (1) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R? is C1-Ce-alkyl. 16. The compound of formula (1) according to claim 15, or a pharmaceutically 10 acceptable salt thereof, wherein R? is methyl. 17. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, halogen, hydroxy, C1-C6-alkyl, 5- to 14-membered heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is 15 optionally substituted with 1 substituent selected from halogen and hydroxy- C1-Ce-alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R®, taken together with the carbon atom to which they are attached, form a C3-Cj0-cycloalkyl; or 20R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Ce-cycloalkyl; R** and R°? are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a C3-Cio-cycloalkyl or oxo; 25 R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Cs-C1o-ary]; wherein said 5- to 14-membered heteroaryl, and C6-Cjo-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3- Cio-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and 30 R’ is selected from hydrogen, C1-Ce-alkyl, halo-C1-C¢-alkyl, and 5- to 14- membered heteroaryl. WO 2025 / 012296 PCT / EP2024 / 069422 - 139 - 18. The compound of formula (1) according to claim 17, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl,1,2,4-triazolyl, 5 and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and R* is selected from hydrogen, fluoro, and methyl; or R* and R®, taken together with the carbon atom to which they are attached, form a cyclopropyl; or 10 R* and R’, taken together with the carbon atoms to which they are attached, form a cyclopropyl; R** and R°® are each independently selected from hydrogen and methyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a cyclopropyl or oxo; 15 R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independently selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; 20 R® is hydrogen; and R’ is selected from hydrogen, methyl, CHF2, CF3, and imidazolyl. 19. The compound of formula (1)according to claim 17, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, halogen, and Ci-Co-alky]; 25 R* is selected from hydrogen and halogen; R* is hydrogen; R° is hydrogen; R® is selected from hydrogen and 5- to 14-membered heteroaryl; wherein said 5- to 14-membered heteroaryl is substituted with 1 substituent selected from 30 halogen, C1-C6-alkyl, C3-C10-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and R’ is selected from hydrogen, halo-C-C¢-alkyl, and 5- to 14-membered heteroaryl. WO 2025 / 012296 PCT / EP2024 / 069422 - 140 - 20. The compound of formula (1) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein: R* is selected from hydrogen, fluoro, and methy]; R* is selected from hydrogen and fluoro; 5 R™ is hydrogen; R°’ is hydrogen; R® is selected from hydrogen, pyridyl, and pyrazolyl; wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from bromo, methyl, cyclopropyl, and pyridyl;10 R® is hydrogen; and R’ _ is selected from hydrogen, CF3, and imidazoly]. 21. The compound of formula (1) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein: U _ isselected from O, S, and NRY; 15 V___isacovalent bond or CHR’; RY is cyano; and RY is halo-Ci-Ce-alkyl. 22. The compound of formula (1) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein: 20 U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: RY is cyano; and RY is CF3. 23. The compound of formula (1) according to claim 22, or a pharmaceutically 25 acceptable salt thereof, wherein U is O and V is a covalent bond, represented by Formula (Ia): Rib R°? R’2 5b RA Ro R RX JL 9 (x ann bey NoveZ OR R pe (Ia) WO 2025 / 012296 PCT / EP2024 / 069422 -141 - wherein X, Y, Z, and R! to R’ are as defined in any one of claims 1 to 20. 24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) Xand Y are CHand Z is CR”; or 5 (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: A is selected from 3- to 6-membered heterocyclyl comprising 1 to 3 heteroatoms 10 selected from N, O, and S, 5- to 6-membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O, and S, phenyl, and C3-C¢-cycloalkyl; L is selected from a covalent bond, -CH2—, and -NR!-: R” is hydrogen; RY is cyano; 15 RY is halo-Ci-Co-alkyl; R“ is selected from hydrogen and C1-Co-alky]; R! _ is selected from hydrogen, halogen, cyano, C1-Co-alkyl, C2-C6-alkynyl, halo- Ci-Ce-alkyl, hydroxy-C1-Ce-alkyl, Ci-Ce-alkoxy, and a group Cory 20 R'* is selected from hydrogen, halogen, C1-Cs-alkyl, and halo-Ci-Ce-alkyl; R** is selected from hydrogen, C1-Co-alkyl, halo-Ci-Co-alkyl, C1-Co-alkyl-NH-C- Co-alkyl-, C3-Cio-cycloalkyl, phenyl-C1-Co6-alkyl, and R*°-O-C-Co-alky]; wherein said phenyl is optionally substituted with 1 halogen substituent; R?> is hydrogen;and 25 R* is selected from hydrogen, C1-C¢-alkyl, halo-Ci-C¢-alkyl, and phenyl; wherein said phenyl is optionally substituted with 1 halogen substituent; or R* and R”°, taken together with the carbon atom to which they are attached, form a C3-Ce-cycloalkyl; R? is selected from C1-C6-alkyl and halo-C1-Co-alkyl; 30 R* is selected from hydrogen, halogen, hydroxy, C1-Ce-alkyl, 5- to 14-membered heteroaryl, and Cs-Ci0-aroyl; wherein said 5- to 14-membered heteroaryl is WO 2025 / 012296 PCT / EP2024 / 069422 - 142 - optionally substituted with 1 substituent selected from halogen and hydroxy- C1-Ce-alkyl; and R* is selected from hydrogen, halogen, and C1-Co-alkyl; or R* and R®, taken together with the carbon atom to which they are attached, form a 5 C3-Cio-cycloalkyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a C3-Ce-cycloalkyl; R** and R°? are each independently selected from hydrogen and C1-Co-alkyl; or R** and R°°, taken together with the carbon atom towhich they are attached, form a 10 C3-Cio-cycloalkyl or oxo; R® is selected from hydrogen, 5- to 14-membered heteroaryl, and Cs-C1o-ary]; wherein said 5- to 14-membered heteroaryl, and C6-Cjo-aryl are substituted with 1-3 substituents independently selected from halogen, Ci-Ce-alkyl, C3- Cio-cycloalkyl, and 5- to 14-membered heteroaryl; 15 R® is hydrogen; and R’ is selected from hydrogen, C1-Ce-alkyl, halo-C1-C¢-alkyl, and 5- to 14- membered heteroaryl. 25. The compound of formula (1) according to claim 24, or a pharmaceutically acceptable salt thereof, wherein: 20 (i) Xand Y are CH and Z is CR”; or (ii) X and Z are CH and Y is N; or (iii) Xis N and Y and Z are CH; U _ isselected from O, S, and NRY; V___isacovalent bond or CHR’: 25 A is selected from azetidine, tetrahydrofurane, tetrahydropyrane, pyrrolidine, pyrazole, phenyl, pyridyl, and cyclopropyl; L is selected from a covalent bond, -CH2—, and -NR!-: R” is hydrogen; RY is cyano; 30 RY is CFs; R“ is selected from hydrogen andmethyl; WO 2025 / 012296 PCT / EP2024 / 069422 - 143 - R! _ is selected from hydrogen, fluoro, chloro, bromo, cyano, methyl, ethyl, prop-1- R'2 L ynyl, hydroxymethyl, CHF2, methoxy, and a group Coy ¥ R!* is selected from hydrogen, chloro, methyl, and and CFs; R** is selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH2xCHF2, CH3N- 5 CH2-, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF2-O-CHo-, CF3-O-CH2-, and cyclopropyl; and R?? is hydrogen; or R* and R”°, taken together with the carbon atom to which they are attached, form a cyclopropyl or a cyclobutyl; 10 R? is selected from methyl and CHF>; R* is selected from hydrogen, fluoro, hydroxy, methyl, benzoyl, pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl; wherein said pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl is optionally substituted with 1 substituent selected from chloro, bromo, and hydroxymethyl; and 15 R* is selected from hydrogen, fluoro, and methyl; or R* and R®, takentogether with the carbon atom to which they are attached, form a cyclopropyl; or R* and R’, taken together with the carbon atoms to which they are attached, form a cyclopropyl; 20 R** and R°® are each independently selected from hydrogen and methyl; or R** and R°°, taken together with the carbon atom to which they are attached, form a cyclopropyl or oxo; R® is selected from hydrogen, pyrazolyl, pyridyl, pyridazinyl, isoxazolyl, 1,2,4- oxadiazolyl, and phenyl; wherein said pyrazolyl, pyridyl, pyridazinyl, 25 isoxazolyl, 1,2,4-oxadiazolyl, and phenyl are substituted with 1-3 substituents independently selected from fluoro, chloro, bromo, methyl, cyclopropyl, and pyridyl; R° is hydrogen; and R’ is selected from hydrogen, methyl, CHF2, CF3, and imidazolyl. 30 26. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, wherein: WO 2025 / 012296 PCT / EP2024 / 069422 - 144 - (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; Us isO; V___isacovalentbond; 5 R! is selected from hydrogen, halogen, and Ci-Co-alky]; R* is Ci-Co-alkyl; and R?’ is hydrogen; R? is Ci-Co-alkyl; R* is selected from hydrogen, halogen, and Ci-Co-alky]; 10 R* is selected from hydrogen and halogen; R* is hydrogen; R° is hydrogen; R® is selected from hydrogen and 5- to 14-membered heteroaryl; wherein said 5- to 14-membered heteroaryl is substituted with 1 substituent selected from 15 halogen, C1-C6-alkyl, C3-C10-cycloalkyl, and 5- to 14-membered heteroaryl; R° is hydrogen; and R’ _ is selected from hydrogen, halo-Ci-Cs-alkyl, and 5- to 14-membered heteroaryl. 27. The compound of formula (1) according to claim 26, or a pharmaceutically 20 acceptable salt thereof, wherein: (i) xX, Y and Z are CH; or (ii) X and Z are CH and Y is N; Us isO; V___isacovalent bond; 25 R! is selected from hydrogen, fluoro, and methy]; R* is methyl; and R?’ is hydrogen; R? is methyl; R* is selected from hydrogen, fluoro, and methy]; 30 R* is selected from hydrogen and fluoro; R* ishydrogen; R° is hydrogen; WO 2025 / 012296 PCT / EP2024 / 069422 - 145 - R® is selected from hydrogen, pyridyl, and pyrazolyl; wherein said pyridyl and pyrazolyl are substituted with 1 substituent selected from bromo, methyl, cyclopropyl, and pyridyl; R° is hydrogen; and 5 R’ is selected from hydrogen, CF3, and imidazolyl. 28. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (1) is selected from: 1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-tetrahydrofuran-3-yl urea; 1-methyl-3-[(3RS, 4RS)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4- 10 pyridyl)ethy]]urea; 1-methyl-3-[(3RS, 4SR)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4- pyridyl)ethyl urea; 1-methyl-1-[(1S)-1-(4-pyridylethyl]-3-[(3RS)-3-(trifluoromethyl)tetrahydrofuran-3- yljurea; 15 3-[(3RS)-3-(1 H-imidazol-2-yl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 1-methyl-3-[(3RS)-3-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl urea; 3-[(2RS,3SR)-2-(5-bromo-3 -pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 20 pyridyl)ethy]]urea; 1-methyl-1-[(1S)-1-(4-pyridy)ethyl]-3-[(2RS,3 SR)-2-[5-(3-pyridyl)-3- pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2RS,3SR)-2-(5-cyclopropy]-3-pyridy|)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1- (4-pyridyl)ethylJurea; 25 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1 S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-y1]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(28,3R)-2-(5-bromo-3 -pyridy1)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 30 pyridyl)ethy]]urea; 3-[(2R,3S)-2-(5-bromo-3 -pyridy1)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 146 - 1-methyl-1-[(1S)-1-(4-pyridylethy]]-3-[(2R,3S)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 1-methyl-1-[(1S)-1-(4-pyridylethy]]-3-[(28,3R)-2-[5-(3-pyridyl)-3- pyridyl]tetrahydrofuran-3-yl]urea; 5 3-[(2R,3S)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 3-[(28,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 1-methyl-1-[(1S)-1-(4-pyridylethyl]-3-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl- 10 ethyl)urea; 1-[(3-chloro-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-fluoro-4-pyridyl)methyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-(4-pyridylmethy])urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 15 pyridyl)propyl]urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4- pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)propyl]urea; 203-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4- pyridyl)propyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methy]]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea; 25 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- 30 ylethylJurea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 147- 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- ylethyl]urea; 5 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4- ylethyl]urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- 10 ylethylJurea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4- ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethy])urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethylurea; 15 3-(4-benzoyltetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl urea; 1-methyl-1-[(1S)-1-(4-pyridylethyl]-3-[(3R)-3-(trifluoromethy])tetrahydrofuran-3- yljurea; 1-methyl-1-[(1S)-1-(4-pyridylethy1]-3-[(3 S)-3-(trifluoromethy])tetrahydrofuran-3- yljurea; 20 1-methyl-1-[(1S)-1-(4-pyridyl)ethy1]-3-[(GR)-3-(trifluoromethy])tetrahydrofuran-3- yljurea; 1-methyl-1-[(1S)-1-(4-pyridylethy1]-3-[(3 S)-3-(trifluoromethy])tetrahydrofuran-3- yljurea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4- 25 pyridyl)methyl urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4- pyridyl)methyl urea; 1-[(3-bromo-4-pyridyl)methy]]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4- 30 ylethylJurea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4- ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4- ylethyl]urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 148 - 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4- ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 5 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1- 10 methyl-urea;3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 15 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1- methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[[3-(hydroxymethyl)-4-pyridyl]methy]]-1- 20 methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4- pyridyl)ethyl urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4- pyridyl)ethyl urea; 25 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1 S)-1-(3-methyl-4- pyridyl)ethyl urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4- pyridyl)ethyl urea; 1-[(3-cyclopropyl-4-pyridyl)methy1]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl- 30 urea;1-[(3-bromo-4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; 1-[(3-bromo-4-pyridyl)methy]]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl- urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 149 - 1-[[3-(azetidin-1-yl)-4-pyridyl]methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1- methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[2-methoxy-1-(4-pyridyl)ethyl]-1-methyl- 5 urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-methoxy-4-pyridyl)methy]]-1-methyl- urea; 1-[1-(3-chloro-4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-pyrrolidin-1-yl-4- 10 pyridyl)methyl urea; 1-[(S)-cyclopropyl(4-pyridyl)methy1]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(S)-cyclopropyl(4-pyridyl)methy1]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 15 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 20 3-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridy])tetrahydrofuran-3-yl]-1-methyl-1-[(1S)- 1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)- 1-(4-pyridyl)ethyl]urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- 25 methyl-urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridyl)ethy]]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 30 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4- pyridyl)cyclopropyl urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 150 -3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4- pyridyl)cyclopropyl urea; 1-[[3-(3-chloroanilino)-4-pyridyl]methy1]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 5 1-[[3-(3-chloroanilino)-4-pyridyl]methy]]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 3-[(3S)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 3-[(3R)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- 10 pyridyl)ethy]]urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4- pyridyl)ethyl urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4- pyridyl)ethyl urea; 15 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4- pyridyl)ethyl urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4- pyridyl)ethyl urea; 1-methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4- 20 pyridyl)ethy]]urea;1-methyl-3-[(1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridyl)ethy]Jurea; 1-methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4- pyridyl)ethyl urea; 1-methyl-3-[(1S,5S)-3-oxabicyclo[3.1.0]hexan-1-yl]-1-[(1S)-1-(4-pyridyl)ethy]Jurea; 25 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]Jurea; 30 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(1H-pyrazol-5-yl)-4- pyridyl ]methyl urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethy]]-1- methyl-urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 151 - 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethyl]-1- methyl-urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridyl)ethy]]-1- methyl-urea; 5 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridyl)ethy]]-1- methyl-urea; 3-[3-(difluoromethyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4- 10 pyridyl)methyl urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4- pyridyl)methyl urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridylethy]]thiourea; 3-(4,4-difluorotetrahydrofuran-3-y1)-1-methyl-1-[[3-(3-methyl-1H-pyrazol-5-yl)-4- 15 pyridyl ]methyl urea; 2-cyano-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl]guanidine; 1-methyl-3-(5-oxotetrahydrofuran-3-yl)-1-[(1S)-1-(4-pyridylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3- 20 yl]methyl]-4-pyridyl]methyl urea;3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3- yl]methyl]-4-pyridyl]methyl urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3 S)-tetrahydrofuran-3- yl]methyl]-4-pyridyl]methyl urea; 25 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3- yl]methyl]-4-pyridyl]methyl urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[[3-(4-pyridyl)-4- pyridyl ]methyl urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[[3-(3-pyridyl)-4- 30 pyridyl ]methyl urea; 1-[[3-(4-chloropheny])-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 1-[[3-(2-chloropheny])-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 152 - 1-[[3-(3-chloropheny])-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 1-[2-(3-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1- methyl-urea; 53-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-prop-1-ynyl-4- pyridyl)methyl urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3 -yl]-1-methyl-1-[[3-(2-pyridyl)-4- pyridyl ]methyl urea; 1-[2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1- 10 methyl-urea; 3-[(3S8,4R)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 3-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4- pyridyl)ethyl urea; 15 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4- ylmethyl)-4-pyridyl]methyl]Jurea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4- ylmethyl)-4-pyridyl]methyl]Jurea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[4- 20 (trifluoromethyl)phenyl]-4-pyridyl]methyl]urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 1-methyl-urea]; 25[3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 1-methyl-urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethy]l-4-pyridyl)ethyl]- 1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 30 1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridylethyl]- 1-methyl-urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 153 - 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridylethyl]- 1-methyl-urea; 5 3-[(3R)-4,4-difluorotetrahydrofuran-3 yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]- 1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridylethyl]- 1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethy]l-4-pyridyl)ethyl]- 10 1-methyl-urea]; 1-[(1S)-1-(3-bromo-4-pyridyl)ethy1!]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(1S)-1-(3-bromo-4-pyridyl)ethyl!]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 15 1-[(1R)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(1R)-1-(-bromo-4-pyridyl)ethyl]-3-[(3 S)-4,4-difluorotetrahydrofuran-3-yl]-1- methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3 S)-4,4- 20 difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4- difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4- difluorotetrahydrofuran-3-yl]-1-methyl-urea; 25 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridylethyl]-3-[(3 S)-4,4- difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4, 4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4- 30 pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1 R)-3-(4-fluorophenyl)-1-(4- pyridyl)propyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4- pyridyl)propyl]-1-methyl-urea; WO 2025 / 012296 PCT / EP2024 / 069422 - 154 - 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 5 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[@R)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[GS)-4,4-difluorotetrahydrofuran-3-yl]- 1-methyl-urea; 1-(difluoromethy1)-3-(4,4-difluorotetrahydrofuran-3-yl)-1-(4-pyridylmethyl)urea; 10 [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea;3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1- 15 methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea; 20 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridylethyl]-1- methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridylethyl]-1- 25 methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridylethyl]-1- methyl-urea]; 30 [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea;3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1- methyl-urea]; and WO 2025 / 012296 PCT / EP2024 / 069422 - 155 - 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2,2,2-trifluoro-1-(4- pyridylethyl]urea]. 29. The compound of formula (1) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active 5 substance. 30. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier. 31. A method of treating or preventing a condition associated with SARM1 in a subject 10 in need thereof, the method comprising administering to the subject a therapeutically effective amount of the compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 30. 32. The method according to claim 31, wherein saidcondition associated with SARM1 15 is a condition affecting the nervous system, including the central nervous system and the peripheral nervous system. 33. The method according to claim 32, wherein said condition affecting the nervous system is neurodegenerative disorder. 34. The method according to claim 31, wherein said condition associated with SARM1 20 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy induced peripheral neuropathy, diabetes induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Tooth disease. 35. Acompound according to any one of claims | to 28, or a pharmaceutically 25 acceptable salt thereof, or a pharmaceutical composition according to claim 30, for use in a method according to any one of claims 31 to 34. 36. Use of a compound according to any one of claims 1 to 28, or of a pharmaceutically acceptable salt thereof, or of a pharmaceutical compositionaccording to claim 30, in a method according to any one of claims 31 to 34. WO 2025 / 012296 PCT / EP2024 / 069422 - 156 - 37. Use of a compound according to any one of claims 1 to 28, or of a pharmaceutically acceptable salt thereof, in the preparation of a medicament for use in a method according to any one of claims 31 to 34. 38. A process of manufacturing a compound of formula (Ia) according to claim 23, or a 5 pharmaceutically acceptable salt thereof, comprising: reacting a first amine 1, wherein R**, R*>, R™, R°>, R°, R®, and R’ are as defined in any one of claims 1 to 28, 4b po RA R R 5b R \e) HN 7\> Re RR 1 with a second amine 3, wherein R!, R*, R*, R3, X, Y, and Z are as defined in any 10 one of claims | to 28, RA RP rN Nv UZ OR “Y 3 in the presence of a base and a urea forming reagent, to form said compound of formula (Ia). 39. A compound of formula (I) according to any one of claims | to 28, when 15 manufactured according to the process of claim 38. 40. The invention as describedhereinbefore. INTERNATIONAL SEARCH REPORT ; International application No PCT / EP2024 / 069422 A. CLASSIFICATION OF SUBJECT MATTER INV. C07D405 / 12 C07D405 / 14 A61P25 / 00 ADD. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) A61P CO7D Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) EPO-I...

Claims

1. A compound of formula (I) (I) Or its pharmaceutically acceptable salt, wherein: X, Y, and Z are each selected from CR Z And N, provided that at most two of X, Y and Z are N; U is selected from O, S, and NR. U ; V is a covalent bond or C(R) V )2; A is selected from 3- to 14-membered heterocyclic groups, 5- to 14-membered heteroaryl groups, and C6-C... 10 -Aryl and C3-C 10 -cycloalkyl; L is selected from covalent bonds, –CH2–, and –NR. L –; R L Selected from hydrogen and C1-C6-alkyl; R U Selected from hydrogen, C1-C6-alkyl, and cyano groups; Each R V Independently selected from hydrogen, C1-C6-alkyl, and halo-C1-C6-alkyl; R Z Selected from hydrogen and C1-C6-alkyl; R 1 Selected from hydrogen, halogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, and groups. ; R 1a Selected from hydrogen, halogens, C1-C6-alkyl, and halo-C1-C6-alkyl; R 2a and R 2b Each is independently selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, C1-C6-alkyl-NH-C1-C6-alkyl-, C3-C 10 -Cycloalkyl, C3-C 10 -cycloalkyl-C1-C6-alkyl, C6-C 10 -Aryl, C6-C 10 -aryl-C1-C6-alkyl and R 2c -O-C1-C6-alkyl; wherein each C6-C 10 -Aryl and C3-C 10 -The cycloalkyl group is optionally substituted with 1 to 2 halogen substituents, or R 2a and R 2b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl; R 2c Selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl and C6-C 10 -Aryl, wherein the C6-C 10 -The aryl group may optionally be substituted with one or two halogen substituents; R 3 Selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl and C3-C 10 -cycloalkyl; R 4a and R 4b Each is independently selected from hydrogen, halogen, hydroxyl, C1-C6-alkyl, 5- to 14-membered heteroaryl, C6-C 10 -Aryl, C6-C 10 -Aromatic acyl, 5- to 14-membered heteroaryl; wherein the 5- to 14-membered heteroaryl, C6-C 10 -Aryl, C6-C 10 -Aromatic acyl group, 5- to 14-membered heteroaromatic acyl group optionally substituted by 1 to 3 independent substituents selected from halogens and hydroxy-C1-C6-alkyl groups; or R 4a and R 4b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl or 3- to 14-membered heterocyclic groups, wherein the C3-C 10 -Cycloalkyl groups and 3- to 14-membered heterocyclic groups are optionally substituted with 1 to 3 halogen substituents; or R 4a and R 7 Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl; R 5a and R 5b Each is independently selected from hydrogen and C1-C6-alkyl; or R 5a and R 5b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl or oxo; R 6a and R 6b Each is independently selected from hydrogen, 5- to 14-membered heteroaryl groups, and C6-C. 10 -aryl; wherein the 5- to 14-membered heteroaryl and C6-C 10 -The aryl group is optionally derived from 1 to 3 independently selected halogens, C1-C6-alkyl groups, halo-C1-C6-alkyl groups, C3-C6-alkyl groups. 10 Substitution with cycloalkyl groups and 5- to 14-membered heteroaryl groups; and R 7 It is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl and 5- to 14-membered heteroaryl groups.

2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH, and Z is CR. Z ;where R Z Selected from hydrogen and C1-C6-alkyl; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH.

3. The compound of formula (I) according to claim 2, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR Z ;where R Z Selected from hydrogen and methyl; or (ii) X and Z are CH and Y is N.

4. The compound of formula (I) according to claim 3, or a pharmaceutically acceptable salt thereof, wherein X, Y and Z are CH.

5. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen, halogen, cyano, C1-C6-alkyl, C2-C6-ynyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy and groups ; A is selected from 3- to 6-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, phenyl and C3-C6-cycloalkyl groups; L is selected from covalent bonds, –CH2–, and –NR. L –; R L It is hydrogen; and R 1a It is selected from hydrogen, halogen, C1-C6-alkyl and halogenated-C1-C6-alkyl.

6. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein: R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, prop-1-ynyl, hydroxymethyl, CHF2, methoxy, and other groups. ; A is selected from azacyclobutane, tetrahydrofuran, tetrahydropyran, pyrrolidine, pyrazole, phenyl, pyridinyl, and cyclopropyl; L is selected from covalent bonds, –CH2–, and –NR. L –; R L It is hydrogen; and R 1a Selected from hydrogen, chlorine, methyl and CF3.

7. The compound of formula (I) according to claim 5, or a pharmaceutically acceptable salt thereof, wherein R 1 It is selected from hydrogen, halogens and C1-C6-alkyl groups.

8. The compound of formula (I) according to claim 7, or a pharmaceutically acceptable salt thereof, wherein R 1 Selected from hydrogen, fluorine, and methyl.

9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein: R 2a Selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl-, C3-C 10 -cycloalkyl, phenyl-C1-C6-alkyl and R 2c -O-C1-C6-alkyl; wherein the phenyl group is optionally substituted with one halogen substituent; R 2b It is hydrogen; and R 2c Selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and phenyl; wherein the phenyl group is optionally substituted with one halogen substituent; or R 2a and R 2b Together with the carbon atoms they are attached to, they form C3-C6-cycloalkyl groups.

10. The compound of formula (I) according to claim 9, or a pharmaceutically acceptable salt thereof, wherein: R 2a Selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH2CHF2, CH3N-CH2-, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF2-O-CH2-, CF3-O-CH2-, and cyclopropyl; and R 2b It is hydrogen; or R 2a and R 2b Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups.

11. The compound of formula (I) according to claim 8, or a pharmaceutically acceptable salt thereof, wherein: R 2a It is a C1-C6-alkyl group; and R 2b It is hydrogen.

12. The compound of formula (I) according to claim 10, or a pharmaceutically acceptable salt thereof, wherein: R 2a It is methyl; and R 2b It is hydrogen.

13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from C1-C6-alkyl and halogenated-C1-C6-alkyl.

14. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R 3 Selected from methyl and CHF2.

15. The compound of formula (I) according to claim 13, or a pharmaceutically acceptable salt thereof, wherein R 3 It is a C1-C6-alkyl group.

16. The compound of formula (I) according to claim 15, or a pharmaceutically acceptable salt thereof, wherein R 3 It is methyl.

17. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein: R 4a Selected from hydrogen, halogen, hydroxyl, C1-C6-alkyl, 5- to 14-membered heteroaryl and C6-C 10 -Aromatic acyl; wherein the 5- to 14-membered heteroaryl group is optionally substituted with one substituent selected from halogens and hydroxy-C1-C6-alkyl groups; and R 4b Selected from hydrogen, halogens, and C1-C6-alkyl groups; or R 4a and R 4b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl; or R 4a and R 7 Together with the carbon atoms they are attached to, they form C3-C6-cycloalkyl groups; R 5a and R 5b Each is independently selected from hydrogen and C1-C6-alkyl; or R 5a and R 5b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl or oxo; R 6a Selected from hydrogen, 5- to 14-membered heteroaryl groups and C6-C 10 -aryl; wherein the 5- to 14-membered heteroaryl and C6-C 10 -Aryl group, independently selected from 1 to 3 alkyl groups, including halogen, C1-C6-alkyl, C3-C6-alkyl, C4-alkyl, C5-alkyl, C6 ... 10 Substitution with cycloalkyl groups and 5- to 14-membered heteroaryl groups; R 6b It is hydrogen; and R 7 It is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl and 5- to 14-membered heteroaryl groups.

18. The compound of formula (I) according to claim 17, or a pharmaceutically acceptable salt thereof, wherein: R 4a The group is selected from hydrogen, fluorine, hydroxyl, methyl, benzoyl, pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl; wherein the pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl groups are optionally substituted with one substituent selected from chlorine, bromine, and hydroxymethyl; and R 4b Selected from hydrogen, fluorine, and methyl; or R 4a and R 4b Together with the carbon atoms they are attached to, they form cyclopropyl groups; or R 4a and R 7 Together with the carbon atoms they are attached to, they form cyclopropyl groups; R 5a and R 5b Each is independently selected from hydrogen and methyl; or R 5a and R 5b Together with the carbon atoms they are attached to, they form cyclopropyl or oxo groups; R 6a The group is selected from hydrogen, pyrazolyl, pyridinyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R 6b It is hydrogen; and R 7 Selected from hydrogen, methyl, CHF2, CF3 and imidazole groups.

19. The compound of formula (I) according to claim 17, or a pharmaceutically acceptable salt thereof, wherein: R 4a Selected from hydrogen, halogens, and C1-C6-alkyl groups; R 4b Selected from hydrogen and halogens; R 5a It is hydrogen; R 5b It is hydrogen; R 6a Selected from hydrogen and 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl group is derived from a halogen, C1-C6-alkyl, C3-C4-alkyl group. 10 Substitution with cycloalkyl groups and 5- to 14-membered heteroaryl groups; R 6b It is hydrogen; and R 7 It is selected from hydrogen, halo-C1-C6-alkyl and 5- to 14-membered heteroaryl groups.

20. The compound of formula (I) according to claim 19, or a pharmaceutically acceptable salt thereof, wherein: R 4a Selected from hydrogen, fluorine, and methyl; R 4b Selected from hydrogen and fluorine; R 5a It is hydrogen; R 5b It is hydrogen; R 6a The group is selected from hydrogen, pyridyl, and pyrazolyl; wherein the pyridyl and pyrazolyl groups are substituted with one substituent selected from bromine, methyl, cyclopropyl, and pyridyl. R 6b It is hydrogen; and R 7 Selected from hydrogen, CF3, and imidazole groups.

21. The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein: U is selected from O, S, and NR. U ; V represents a covalent bond or CHR. V ; R U It is cyano; and R V It is a halogenated-C1-C6-alkyl group.

22. The compound of formula (I) according to claim 21, or a pharmaceutically acceptable salt thereof, wherein: U is selected from O, S, and NR. U ; V represents a covalent bond or CHR. V ; R U It is cyano; and R V It is CF3.

23. The compound of formula (I) according to claim 22, or a pharmaceutically acceptable salt thereof, wherein U is O and V is covalently bonded, said compound of formula (I) is represented by formula (Ia): (him) Where X, Y, Z and R 1 To R 7 As defined in any one of claims 1 to 20.

24. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR Z ; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S, and NR. U ; V represents a covalent bond or CHR. V ; A is selected from 3- to 6-membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O and S, 5- to 6-membered heteroaryl groups containing 1 to 3 heteroatoms selected from N, O and S, phenyl and C3-C6-cycloalkyl groups; L is selected from covalent bonds, –CH2–, and –NR. L –; R L It is hydrogen; R U It is cyano; R V It is a halogenated-C1-C6-alkyl group; R Z Selected from hydrogen and C1-C6-alkyl; R 1 Selected from hydrogen, halogen, cyano, C1-C6-alkyl, C2-C6-ynyl, halo-C1-C6-alkyl, hydroxy-C1-C6-alkyl, C1-C6-alkoxy and groups ; R 1a Selected from hydrogen, halogens, C1-C6-alkyl, and halo-C1-C6-alkyl; R 2a Selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl-, C3-C 10 -cycloalkyl, phenyl-C1-C6-alkyl and R 2c -O-C1-C6-alkyl; wherein the phenyl group is optionally substituted with one halogen substituent; R 2b It is hydrogen; and R 2c Selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl, and phenyl; wherein the phenyl group is optionally substituted with one halogen substituent; or R 2a and R 2b Together with the carbon atoms they are attached to, they form C3-C6-cycloalkyl groups; R 3 Selected from C1-C6-alkyl and halo-C1-C6-alkyl; R 4a Selected from hydrogen, halogen, hydroxyl, C1-C6-alkyl, 5- to 14-membered heteroaryl and C6-C 10 -Aromatic acyl; wherein the 5- to 14-membered heteroaryl group is optionally substituted with one substituent selected from halogens and hydroxy-C1-C6-alkyl groups; and R 4b Selected from hydrogen, halogens, and C1-C6-alkyl groups; or R 4a and R 4b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl; or R 4a and R 7 Together with the carbon atoms they are attached to, they form C3-C6-cycloalkyl groups; R 5a and R 5b Each is independently selected from hydrogen and C1-C6-alkyl; or R 5a and R 5b Together with the carbon atoms they are attached to, they form C3-C. 10 -cycloalkyl or oxo; R 6a Selected from hydrogen, 5- to 14-membered heteroaryl groups and C6-C 10 -aryl; wherein the 5- to 14-membered heteroaryl and C6-C 10 -Aryl group, independently selected from 1 to 3 alkyl groups, including halogen, C1-C6-alkyl, C3-C6-alkyl, C4-alkyl, C5-alkyl, C6 ... 10 Substitution with cycloalkyl groups and 5- to 14-membered heteroaryl groups; R 6b It is hydrogen; and R 7 It is selected from hydrogen, C1-C6-alkyl, halo-C1-C6-alkyl and 5- to 14-membered heteroaryl groups.

25. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, wherein: (i) X and Y are CH and Z is CR Z ; or (ii) X and Z are CH and Y is N; or (iii) X is N and Y and Z are CH; U is selected from O, S, and NR. U ; V represents a covalent bond or CHR. V ; A is selected from azacyclobutane, tetrahydrofuran, tetrahydropyran, pyrrolidine, pyrazole, phenyl, pyridinyl, and cyclopropyl; L is selected from covalent bonds, –CH2–, and –NR. L –; R L It is hydrogen; R U It is cyano; R V For CF3; R Z Selected from hydrogen and methyl; R 1 Selected from hydrogen, fluorine, chlorine, bromine, cyano, methyl, ethyl, prop-1-ynyl, hydroxymethyl, CHF2, methoxy, and other groups. ; R 1a Selected from hydrogen, chlorine, methyl, and CF3; R 2a Selected from hydrogen, methyl, ethyl, CH2F, CHF2, CF3, CH2CHF2, CH3N-CH2-, hydroxymethyl, methoxymethyl, phenoxymethyl, chlorophenoxymethyl, fluorophenylethyl, CHF2-O-CH2-, CF3-O-CH2-, and cyclopropyl; and R 2b It is hydrogen; or R 2a and R 2b Together with the carbon atoms they are attached to, they form cyclopropyl or cyclobutyl groups; R 3 Selected from methyl and CHF2; R 4a The group is selected from hydrogen, fluorine, hydroxyl, methyl, benzoyl, pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl; wherein the pyridyl, triazolyl, 1,2,4-triazolyl, and pyrazolyl groups are optionally substituted with one substituent selected from chlorine, bromine, and hydroxymethyl; and R 4b Selected from hydrogen, fluorine, and methyl; or R 4a and R 4b Together with the carbon atoms they are attached to, they form cyclopropyl groups; or R 4a and R 7 Together with the carbon atoms they are attached to, they form cyclopropyl groups; R 5a and R 5b Each is independently selected from hydrogen and methyl; or R 5a and R 5b Together with the carbon atoms they are attached to, they form cyclopropyl or oxo groups; R 6a The group is selected from hydrogen, pyrazolyl, pyridinyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl; wherein the pyrazolyl, pyridinyl, pyridazinyl, isoxazolyl, 1,2,4-oxadiazolyl and phenyl are substituted with 1 to 3 substituents independently selected from fluorine, chlorine, bromine, methyl, cyclopropyl and pyridinyl; R 6b It is hydrogen; and R 7 Selected from hydrogen, methyl, CHF2, CF3 and imidazole groups.

26. The compound of formula (I) according to claim 24, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y, and Z are CH; or (ii) X and Z are CH and Y is N; U is O; V represents a covalent bond; R 1 Selected from hydrogen, halogens, and C1-C6-alkyl groups; R 2a It is a C1-C6-alkyl group; and R 2b It is hydrogen; R 3 It is a C1-C6 alkyl group; R 4a Selected from hydrogen, halogens, and C1-C6-alkyl groups; R 4b Selected from hydrogen and halogens; R 5a It is hydrogen; R 5b It is hydrogen; R 6a Selected from hydrogen and 5- to 14-membered heteroaryl groups; wherein the 5- to 14-membered heteroaryl group is derived from a halogen, C1-C6-alkyl, C3-C4-alkyl group. 10 Substitution with cycloalkyl groups and 5- to 14-membered heteroaryl groups; R 6b It is hydrogen; and R 7 It is selected from hydrogen, halo-C1-C6-alkyl and 5- to 14-membered heteroaryl groups.

27. The compound of formula (I) according to claim 26, or a pharmaceutically acceptable salt thereof, wherein: (i) X, Y, and Z are CH; or (ii) X and Z are CH and Y is N; U is O; V represents a covalent bond; R 1 Selected from hydrogen, fluorine, and methyl; R 2a It is methyl; and R 2b It is hydrogen; R 3 It is methyl; R 4a Selected from hydrogen, fluorine, and methyl; R 4b Selected from hydrogen and fluorine; R 5a It is hydrogen; R 5b It is hydrogen; R 6a The group is selected from hydrogen, pyridyl, and pyrazolyl; wherein the pyridyl and pyrazolyl groups are substituted with one substituent selected from bromine, methyl, cyclopropyl, and pyridyl. R 6b It is hydrogen; and R 7 Selected from hydrogen, CF3, and imidazole groups.

28. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from: 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-tetrahydrofuran-3-yl]urea; 1-Methyl-3-[(3RS,4RS)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(3RS,4SR)-4-methyltetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3RS)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3RS)-3-(1H-imidazol-2-yl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(3RS)-3-(1-methylpyrazol-4-yl)tetrahydrofuran-3-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2RS,3SR)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2RS,3SR)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2RS,3SR)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2R,3S)-2-(5-bromo-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2R,3S)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(2S,3R)-2-[5-(3-pyridyl)-3-pyridyl]tetrahydrofuran-3-yl]urea; 3-[(2R,3S)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-cyclopropyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-(2,2,2-trifluoro-1-tetrahydrofuran-3-yl-ethyl)urea; 1-[(3-chloro-4-pyridinyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-fluoro-4-pyridyl)methyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-(4-pyridylmethyl)urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)propyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(4-pyridyl)propyl]urea; 3-(4,4-Difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyridazin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-(4-pyridylmethyl)urea; 3-(4-benzoyltetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3R)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 1-Methyl-1-[(1S)-1-(4-pyridyl)ethyl]-3-[(3S)-3-(trifluoromethyl)tetrahydrofuran-3-yl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-methyl-4-pyridyl)methyl]urea; 1-[(3-bromo-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-pyrimidin-4-ylethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-pyrimidin-4-ylethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-fluoro-4-pyridyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[[3-(hydroxymethyl)-4-pyridyl]methyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(3-methyl-4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-1-(3-methyl-4-pyridyl)ethyl]urea; 1-[(3-cyclopropyl-4-pyridyl)methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 1-[(3-bromo-4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(3-bromo-4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(azacyclobutan-1-yl)-4-pyridyl]methyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[2-methoxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-[(3-methoxy-4-pyridyl)methyl]-1-methyl-urea; 1-[1-(3-chloro-4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-Difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-pyrrolidone-1-yl-4-pyridinyl)methyl]urea; 1-[(S)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(S)-cyclopropyl(4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(R)-cyclopropyl(4-pyridyl)methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 3-[(2R,3S)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(2S,3R)-2-(5-bromo-2-methyl-3-pyridyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-chloro-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclopropyl]urea; 1-[[3-(3-chloroanilino)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(3-chloroanilino)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluoro-3-methyl-tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1R)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(1S)-2-phenoxy-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hexane-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1S,5S)-3-oxabicyclo[3.1.0]hexane-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1R,5R)-3-oxabicyclo[3.1.0]hexane-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-Methyl-3-[(1S,5S)-3-oxabicyclo[3.1.0]hexane-1-yl]-1-[(1S)-1-(4-pyridyl)ethyl]urea; 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(difluoromethyl)-4-pyridyl]methyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[1-(4-pyridyl)cyclobutyl]urea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(1H-pyrazol-5-yl)-4-pyridinyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-2-hydroxy-1-(4-pyridyl)ethyl]-1-methyl-urea; 3-[3-(difluoromethyl)tetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[(3-phenyl-4-pyridyl)methyl]urea; 3-(4,4-Difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]thiourea; 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[[3-(3-methyl-1H-pyrazol-5-yl)-4-pyridinyl]methyl]urea; 2-Cyano-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]guanidine; 1-Methyl-3-(5-oxotetrahydrofuran-3-yl)-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3S)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[[(3R)-tetrahydrofuran-3-yl]methyl]-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(4-pyridyl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(3-pyridyl)-4-pyridyl]methyl]urea; 1-[[3-(4-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(2-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[[3-(3-chlorophenyl)-4-pyridyl]methyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[2-(3-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-(4,4-Difluorotetrahydrofuran-3-yl)-1-methyl-1-[(3-prop-1-ynyl-4-pyridyl)methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(2-pyridyl)-4-pyridyl]methyl]urea; 1-[2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-urea; 3-[(3S,4R)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3R,4S)-4-hydroxytetrahydrofuran-3-yl]-1-methyl-1-[(1S)-1-(4-pyridyl)ethyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-(tetrahydropyran-4-ylmethyl)-4-pyridyl]methyl]urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-1-[[3-[4-(trifluoromethyl)phenyl]-4-pyridyl]methyl]urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3,5-dimethyl-4-pyridyl)ethyl]-1-methyl-urea]; 1-[(1S)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-1-(3-bromo-4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-2-(4-chlorophenoxy)-1-(4-pyridyl)ethyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-3-(4-fluorophenyl)-1-(4-pyridyl)propyl]-1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1S)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-[(1R)-3,3-difluoro-1-(4-pyridyl)propyl]-3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-methyl-urea; 1-(difluoromethyl)-3-(4,4-difluorotetrahydrofuran-3-yl)-1-(4-pyridylmethyl)urea; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; [3-[(3R)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1S)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea; 3-[(3S)-4,4-difluorotetrahydrofuran-3-yl]-1-[(1R)-1-(3-ethyl-4-pyridyl)ethyl]-1-methyl-urea]; and 3-(4,4-difluorotetrahydrofuran-3-yl)-1-methyl-1-[2,2,2-trifluoro-1-(4-pyridyl)ethyl]urea].

29. The compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, used as a therapeutically active substance.

30. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

31. A method for treating or preventing a condition associated with SARM1 in a subject of need, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30.

32. The method of claim 31, wherein the condition associated with SARM1 is a condition affecting the nervous system, the nervous system including the central nervous system and the peripheral nervous system.

33. The method of claim 32, wherein the condition affecting the nervous system is a neurodegenerative disease.

34. The method of claim 31, wherein the condition associated with SARM1 is selected from amyotrophic lateral sclerosis, spinal muscular atrophy, chemotherapy-induced peripheral neuropathy, diabetes-induced peripheral neuropathy, multiple sclerosis, Parkinson's disease, glaucoma, stroke, traumatic brain injury, and Charcot-Marie-Toos disease.

35. The compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, for use in the method of any one of claims 31 to 34.

36. Use of the compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 30, in the method of any one of claims 31 to 34.

37. Use of any compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for use in any one of claims 31 to 34.

38. A method for manufacturing a compound of formula (Ia) according to claim 23 or a pharmaceutically acceptable salt thereof, the method comprising: Make the first amine 1, wherein R 4a R 4b R 5a R 5b R 6a R 6b and R 7 As defined in any one of claims 1 to 28, With the second amine 3, where R 1 R 2a R 2b R 3 X, Y, and Z are as defined in any one of claims 1 to 28. The reaction occurs in the presence of alkali and urea-forming agents. To form the compound of formula (Ia).

39. The compound of formula (I) according to any one of claims 1 to 28, manufactured according to the method of claim 38.

40. The present invention as described above.